This document describes research into developing a single chemical entity that can deliver two antimalarial drugs through independent mechanisms of action. Specifically, it details the synthesis of endoperoxide-carbonyl inhibitor hybrid molecules designed to target the malaria parasite. Upon decomposition by heme or ferrous iron in the parasite, these hybrids are intended to simultaneously release a potentially cytotoxic carbon-centered radical as well as a cysteine protease inhibitor, targeting the parasite through two pathways and reducing the risk of resistance development. The researchers synthesized both carbonyl-containing peptide inhibitors and 1,2,4-trioxolane prodrugs, finding that the aldehyde and ketone versions showed nanomolar inhibitory activity against falcipain cysteine proteases
1) Researchers developed anthranilic acid sulfonamides as inhibitors of methionine aminopeptidase-2 (MetAP2), a potential cancer therapy target. Initial compounds had micromolar affinity for MetAP2 but also extensively bound to human serum albumin (HSA), limiting cellular activity.
2) Using protein crystal structures of compounds bound to MetAP2 and HSA, researchers designed modifications to reduce HSA binding by adding a positively charged tertiary amine to the compounds. This reduced the HSA shift in potency while maintaining MetAP2 inhibition.
3) Various linkers connecting the amine to the core structure were evaluated. Compounds with an alkenyl linker
This document describes the design, synthesis, and evaluation of 4-[(4-cyano-2-arylbenzyloxy)-(3-methyl-3H-imidazol-4-yl)methyl]benzonitriles as potent and selective farnesyltransferase (FTase) inhibitors. A previous compound, A315493, was a potent FTase inhibitor but also inhibited geranylgeranyltransferase-I (GGTase-I). The authors designed new compounds by moving the naphthyl group of A315493 to improve selectivity. Compound 16 was found to have improved selectivity while maintaining potency. Further structure-activity relationship studies led to the discovery of compound 64
This study synthesized a series of hydroxy-substituted chalcone oxime derivatives and evaluated their inhibitory effects on tyrosinase and melanin formation in mouse melanoma cells. Two compounds exhibited much stronger tyrosinase inhibition than the positive control kojic acid. Kinetic studies showed that these compounds act as competitive tyrosinase inhibitors by binding to the enzyme's active site. Both compounds inhibited tyrosinase activity and melanin production in mouse melanoma cells, suggesting their potential as skin lightening agents.
This document describes the design, synthesis, and evaluation of a series of 1,3-disubstituted pyrrolo[2,3-b]quinoxalines as potential inhibitors of phosphodiesterase 4 (PDE4) and cancer cell growth. A ligand- and phase transfer catalyst-free intramolecular Heck reaction was used to synthesize the target compounds. Some compounds showed significant inhibition of PDE4B and growth inhibition of oral cancer cells in vitro. They also showed acceptable safety profiles in zebrafish embryos, but no apoptosis was observed. The goal was to develop PDE4 inhibitors that do not inhibit luciferase, which could produce false positives in assays.
Analog design is usually defined as the modification of a drug molecule or of any bioactive compound in order to prepare a new molecule showing chemical and biological similarity with the original model compound
The document describes the design, synthesis, and testing of novel lipopeptide conjugates as potential antimicrobial agents. A library of conjugates was designed based on a template consisting of a hydrophobic moiety, dipeptide, and spermidine. Conjugates containing linoleic acid exhibited potent antibacterial activity against both Gram-positive and Gram-negative bacteria. Structure-activity relationships revealed that optimal activity required a hydrophobicity of 50-70% and a minimum charge of +2. Active conjugates were found to have different modes of action, damaging bacterial cell membranes and DNA. Two conjugates showed selective membrane disruption of pathogenic MRSA and were identified as promising leads for further optimization and development as antimicrobial agents.
This document discusses molecular variation in homologous series and isosteric replacements for drug discovery. It defines homologous series as molecules that differ by a methylene group, such as monoalkylated derivatives and cyclopolymethylenic compounds. Biological activity often follows a bell-shaped curve with increasing carbon chain length, peaking at an optimal partition coefficient for membrane crossing. Isosteric replacements involve substituting atoms or groups with others of similar size and electronic properties, allowing modification while maintaining biological activity, as seen with clozapine analogs. The concepts of homologous series and isosteric replacements are important tools in medicinal chemistry for analog design and drug discovery.
This document describes the synthesis and in vitro anticancer screening of novel 2-amino benzothiazole derivatives. Several 2-amino benzothiazole compounds were synthesized and tested against nine cancer cell lines. Compound 4i showed promising antitumor activity, with a GI50 value of 7.18 × 10−8 M against non-small cell lung cancer cells. Computational docking was performed to explore if these compounds bind similarly to EGFR inhibitors in the ATP binding site. The synthesized compounds were characterized using techniques such as IR, NMR and HRMS.
1) Researchers developed anthranilic acid sulfonamides as inhibitors of methionine aminopeptidase-2 (MetAP2), a potential cancer therapy target. Initial compounds had micromolar affinity for MetAP2 but also extensively bound to human serum albumin (HSA), limiting cellular activity.
2) Using protein crystal structures of compounds bound to MetAP2 and HSA, researchers designed modifications to reduce HSA binding by adding a positively charged tertiary amine to the compounds. This reduced the HSA shift in potency while maintaining MetAP2 inhibition.
3) Various linkers connecting the amine to the core structure were evaluated. Compounds with an alkenyl linker
This document describes the design, synthesis, and evaluation of 4-[(4-cyano-2-arylbenzyloxy)-(3-methyl-3H-imidazol-4-yl)methyl]benzonitriles as potent and selective farnesyltransferase (FTase) inhibitors. A previous compound, A315493, was a potent FTase inhibitor but also inhibited geranylgeranyltransferase-I (GGTase-I). The authors designed new compounds by moving the naphthyl group of A315493 to improve selectivity. Compound 16 was found to have improved selectivity while maintaining potency. Further structure-activity relationship studies led to the discovery of compound 64
This study synthesized a series of hydroxy-substituted chalcone oxime derivatives and evaluated their inhibitory effects on tyrosinase and melanin formation in mouse melanoma cells. Two compounds exhibited much stronger tyrosinase inhibition than the positive control kojic acid. Kinetic studies showed that these compounds act as competitive tyrosinase inhibitors by binding to the enzyme's active site. Both compounds inhibited tyrosinase activity and melanin production in mouse melanoma cells, suggesting their potential as skin lightening agents.
This document describes the design, synthesis, and evaluation of a series of 1,3-disubstituted pyrrolo[2,3-b]quinoxalines as potential inhibitors of phosphodiesterase 4 (PDE4) and cancer cell growth. A ligand- and phase transfer catalyst-free intramolecular Heck reaction was used to synthesize the target compounds. Some compounds showed significant inhibition of PDE4B and growth inhibition of oral cancer cells in vitro. They also showed acceptable safety profiles in zebrafish embryos, but no apoptosis was observed. The goal was to develop PDE4 inhibitors that do not inhibit luciferase, which could produce false positives in assays.
Analog design is usually defined as the modification of a drug molecule or of any bioactive compound in order to prepare a new molecule showing chemical and biological similarity with the original model compound
The document describes the design, synthesis, and testing of novel lipopeptide conjugates as potential antimicrobial agents. A library of conjugates was designed based on a template consisting of a hydrophobic moiety, dipeptide, and spermidine. Conjugates containing linoleic acid exhibited potent antibacterial activity against both Gram-positive and Gram-negative bacteria. Structure-activity relationships revealed that optimal activity required a hydrophobicity of 50-70% and a minimum charge of +2. Active conjugates were found to have different modes of action, damaging bacterial cell membranes and DNA. Two conjugates showed selective membrane disruption of pathogenic MRSA and were identified as promising leads for further optimization and development as antimicrobial agents.
This document discusses molecular variation in homologous series and isosteric replacements for drug discovery. It defines homologous series as molecules that differ by a methylene group, such as monoalkylated derivatives and cyclopolymethylenic compounds. Biological activity often follows a bell-shaped curve with increasing carbon chain length, peaking at an optimal partition coefficient for membrane crossing. Isosteric replacements involve substituting atoms or groups with others of similar size and electronic properties, allowing modification while maintaining biological activity, as seen with clozapine analogs. The concepts of homologous series and isosteric replacements are important tools in medicinal chemistry for analog design and drug discovery.
This document describes the synthesis and in vitro anticancer screening of novel 2-amino benzothiazole derivatives. Several 2-amino benzothiazole compounds were synthesized and tested against nine cancer cell lines. Compound 4i showed promising antitumor activity, with a GI50 value of 7.18 × 10−8 M against non-small cell lung cancer cells. Computational docking was performed to explore if these compounds bind similarly to EGFR inhibitors in the ATP binding site. The synthesized compounds were characterized using techniques such as IR, NMR and HRMS.
1) A series of mefenamic acid-derived 1,2,3-triazole compounds were designed and synthesized via a greener copper-catalyzed azide-alkyne cycloaddition reaction. This yielded a library of 20 novel compounds in good to excellent yields.
2) Three compounds (5d, 5p, and 5q) showed promising apoptotic activity in zebrafish embryos, inducing apoptosis in a dose-dependent manner. Compound 5p showed consistent activity up to 30 mM without causing mortality.
3) One of these compounds may have potential medicinal value based on its apoptotic properties and safety profile observed in zebrafish screening. Further optimization and testing of these
This document provides an overview of molecular variation in homologous series and isosteric replacements for medicinal chemistry. It discusses different types of molecular variations such as variations based on homologous series with different biological response curves. It also discusses isosteric replacements, including the history and development of isosterism concepts. Current isosteric and bioisosteric modifications are presented. The document also discusses molecular variations based on ring transformations, homodimer and heterodimer ligands using the twin drug approach, and molecular variations in medicinal chemistry applications.
This document summarizes research exploring the structure and function of HMG-CoA reductase (HMGR) in Burkholderia cenocepacia. Key findings include:
1) B. cenocepacia HMGR (BcHMGR) exhibits properties of a morpheein, meaning it can exist in multiple quaternary structure states that influence enzymatic activity.
2) The equilibrium between BcHMGR structure states is affected by factors like ligand concentration, enzyme concentration, and pH.
3) BcHMGR preferentially catalyzes the oxidation of mevalonate to HMG-CoA, unlike most HMGRs which catalyze the reverse reaction.
1) Adamantyl-tethered-biphenylic compounds were synthesized and found to induce apoptosis in cancer cells.
2) Compound 30-(adamantan-1-yl)-40-methoxy-[1,10-biphenyl]-3-ol (AMB) showed cytotoxic activity against hepatocellular carcinoma cell lines without harming normal cells.
3) AMB was found to target and downregulate anti-apoptotic Bcl-2 family proteins like Bcl-2 and Bcl-xL, leading to cell cycle arrest and induction of apoptosis in cancer cells.
This document describes the synthesis and anticancer activity of novel 1,2,3-triazole derivatives tethered to a 1,2-benzisoxazole scaffold. Specifically:
- Compounds were synthesized via copper-catalyzed azide-alkyne cycloaddition between benzisoxazole-3-azide and various alkynes.
- The most potent compound, PTB, showed low micromolar anticancer activity against acute myeloid leukemia cell lines via apoptosis induction and cell cycle arrest.
- PTB was found to inhibit histone deacetylases, leading to increased acetylation of histone H3 and tubulin, as well as upregulation of p21
This document summarizes 16 peer-reviewed articles related to the research of Thomas Ruhland. The articles cover a range of topics including electrochemical grafting of TiO2 photoanodes, new tools for high-throughput organic synthesis, the racemization mechanism of chiral organolithium compounds, the discovery of an antidepressant compound, and the identification of new non-peptidic NK3 receptor antagonists. Thomas Ruhland is an author on several of the articles and his research involved developing new synthetic methods and applying them to medicinal chemistry projects.
The bulbs and aerial parts of Zephyranthes concolor were found to contain six alkaloids: chlidanthine, galanthamine, galanthamine N-oxide, lycorine, galwesine, and epinorgalanthamine. High resolution 1H and 13C NMR spectra were recorded for chlidanthine, which was identified through 2D NMR experiments and X-ray crystallography. Chlidanthine and galanthamine N-oxide showed acetylcholinesterase inhibitory activity, though weaker than galanthamine. The alkaloids also showed poor anti-HIV activity and low cytotoxicity.
This document describes a study that synthesized a new class of tyrosinase inhibitors called azachalcones. Azachalcone derivatives were tested for their ability to inhibit the enzyme tyrosinase, which is involved in melanin biosynthesis. Two compounds that were reduction products of pyridinyl azachalcones strongly inhibited tyrosinase activity and were more potent inhibitors than the positive control kojic acid. Kinetic studies showed that these two compounds act as competitive inhibitors of tyrosinase by binding to the enzyme's active site. This new class of azachalcone inhibitors could potentially be used as depigmenting agents or to prevent browning in foods.
Basic Concepts Of Retrosynthesis (Part1)munirnizami
1. The document discusses the basic concepts of retrosynthetic analysis in organic synthesis. Retrosynthesis is the process of working backward from a target molecule to design synthetic routes using disconnections and functional group interconversions.
2. Key concepts include synthons, which are idealized fragments formed by imagined bond cleavages, and synthetic equivalents, which are actual reagents that can function as those synthons.
3. Effective retrosynthesis requires understanding reaction mechanisms and reliable reactions, as well as considering availability of starting materials and stereochemistry.
1) Molecular simulations were used to analyze the mode of inhibition of three pesticides (baygon, metacrate, and velpar) on firefly luciferase. The simulations revealed that the pesticides share the same binding site in the luciferin pocket of luciferase.
2) Experiments were conducted to determine the toxicities of the three individual pesticides and 15 binary mixtures on firefly luciferase bioluminescence. Concentration addition modeling was able to predict the toxicities of the mixtures based on the molecular simulation results.
3) There was a linear relationship found between the calculated binding free energy of the mixtures from the individual pesticide components, and the median effective concentrations of the mixtures in experiments.
1) A solid-phase method for synthesizing oxazolidinones is described which uses solid-phase activation/cycloelimination (SP/ACE). This involves attaching a 1,2-diol to a polymer-bound sulfonyl chloride, reacting one alcohol with an isocyanate, then cycloelimination to form the oxazolidinone.
2) A variety of oxazolidinones were synthesized in good overall yields using this method by changing the R groups on the isocyanate and diol substrates. Enantiopure oxazolidinones were also prepared using a chiral diol derived from D-mannitol.
3) The azidomethyl groups
Bioisosterism is a strategy used in drug design that involves replacing one chemical group with another that has similar physical or chemical properties. This is done to improve properties like potency, selectivity, toxicity, and pharmacokinetics without significantly changing the chemical structure. Common bioisosteric replacements include replacing hydrogen with fluorine, replacing carboxylic acids with amides or esters, or replacing phenyl rings with heteroaromatic or saturated rings. The application of bioisosterism has been an important concept in medicinal chemistry for nearly 80 years and will continue to play a role in drug discovery and optimization.
This document discusses complexation and protein binding. It defines complex compounds as molecules where some bonds cannot be described by classical valence theory. Complexation is the association of two molecules to form a non-covalently bonded entity with a stoichiometry. Ligands interact with central metal ions or atoms via coordinate bonds to form metal complexes. Protein binding is the formation of drug-protein complexes. Factors affecting protein binding include the drug's physicochemical properties, protein concentration and binding sites, drug interactions, and patient characteristics like age and disease state. Kinetics of protein binding influence drug absorption, distribution, metabolism, and elimination.
This document describes research on the synthesis of anti-1,2-diols using aldehyde α-oxygenation followed by organometallic addition. Contrary to previous reports, the researchers found this method produces anti-diols, not syn-diols. They demonstrated the scope of the reaction using different organometallic reagents and applied it to synthesize stereoisomers of oxylipins from a plant, determining the stereochemistry of two natural products. The synthesis involved aldehyde α-oxygenation, organometallic addition, functional group manipulations and comparisons to natural products to assign stereochemistry.
Three symmetrical and two unsymmetrical Schiff bases were synthesized from o-phenylenediamine and substituted salicylaldehydes. The compounds were characterized using various analytical techniques and their antimicrobial activity was tested against bacteria. The symmetrical compounds showed dependence of activity on substituents as H>NO2>Br, while unsymmetrical compounds exhibited higher activity compared to symmetrical ones. The nitro-substituted unsymmetrical compound showed the best antimicrobial properties.
Synthesis of 2-[{4-(t-amino-1-yl)but-2-yn-1-yl }oxy]-1,3-benzothiazole deriva...iosrphr_editor
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
This document summarizes a study that evaluated a glycopeptide esterification method to better estimate sialylation levels and differentiate sialic acid linkages in monoclonal antibodies by MALDI-TOF mass spectrometry. Glycopeptides isolated from tryptic digests of monoclonal antibodies were ethyl esterified. Esterification neutralized sialic acids and decreased metastable fragmentation, allowing more accurate quantification of sialylation. Esterification patterns also enabled differentiation of α2,3 and α2,6 sialic acid linkages. The method was demonstrated to be fast, simple, and effective for monoclonal antibody glycopeptide analysis.
1) Radical retrosynthesis uses one-electron disconnections to simplify synthesis, avoiding protecting groups, functional group interconversions, and redox steps. This enables more direct and minimal syntheses.
2) Radical cross-coupling reactions allow forming C-C and C-X bonds through hydrogen atom transfer or coupling of radicals with redox-active esters, sulfones, or other species. This provides unique chemoselectivity advantages over polar pathways.
3) Case studies demonstrate strategic benefits of radical cross-coupling for synthesis ideality, efficiency, selectivity, and modularity by opening new retrosynthetic opportunities not accessible through two-electron analysis.
stereochemistry and drug action ; basic introduction about stereochemistry and stereoisomers ; pharmacokinetic and pharmacodynamics concept of stereochemistry ; easson Stedman hypothesis ; stereo selectivity criteria .
Shenzhen Guohui lighting Equipment Co., Ltd Allen huang
LED corn light, highbay and floodlight manufacturer ! top quality with competitive price , 3-5 years warranty , at least 120LM/W , help you save 50-70% energy costs !
Allen Huang
sales Director
Shenzhen Guohui Lighting Equipment Co,.Ltd
Tel: 0755-89728339 Fax:0755-89728319
Mob:+8613714593862 Skype :huanglong266 QQ; 2278051053
E-mail : allen@szguohui.com guohui@szguohui.com
Website : www.guohui-light.com
1) A series of mefenamic acid-derived 1,2,3-triazole compounds were designed and synthesized via a greener copper-catalyzed azide-alkyne cycloaddition reaction. This yielded a library of 20 novel compounds in good to excellent yields.
2) Three compounds (5d, 5p, and 5q) showed promising apoptotic activity in zebrafish embryos, inducing apoptosis in a dose-dependent manner. Compound 5p showed consistent activity up to 30 mM without causing mortality.
3) One of these compounds may have potential medicinal value based on its apoptotic properties and safety profile observed in zebrafish screening. Further optimization and testing of these
This document provides an overview of molecular variation in homologous series and isosteric replacements for medicinal chemistry. It discusses different types of molecular variations such as variations based on homologous series with different biological response curves. It also discusses isosteric replacements, including the history and development of isosterism concepts. Current isosteric and bioisosteric modifications are presented. The document also discusses molecular variations based on ring transformations, homodimer and heterodimer ligands using the twin drug approach, and molecular variations in medicinal chemistry applications.
This document summarizes research exploring the structure and function of HMG-CoA reductase (HMGR) in Burkholderia cenocepacia. Key findings include:
1) B. cenocepacia HMGR (BcHMGR) exhibits properties of a morpheein, meaning it can exist in multiple quaternary structure states that influence enzymatic activity.
2) The equilibrium between BcHMGR structure states is affected by factors like ligand concentration, enzyme concentration, and pH.
3) BcHMGR preferentially catalyzes the oxidation of mevalonate to HMG-CoA, unlike most HMGRs which catalyze the reverse reaction.
1) Adamantyl-tethered-biphenylic compounds were synthesized and found to induce apoptosis in cancer cells.
2) Compound 30-(adamantan-1-yl)-40-methoxy-[1,10-biphenyl]-3-ol (AMB) showed cytotoxic activity against hepatocellular carcinoma cell lines without harming normal cells.
3) AMB was found to target and downregulate anti-apoptotic Bcl-2 family proteins like Bcl-2 and Bcl-xL, leading to cell cycle arrest and induction of apoptosis in cancer cells.
This document describes the synthesis and anticancer activity of novel 1,2,3-triazole derivatives tethered to a 1,2-benzisoxazole scaffold. Specifically:
- Compounds were synthesized via copper-catalyzed azide-alkyne cycloaddition between benzisoxazole-3-azide and various alkynes.
- The most potent compound, PTB, showed low micromolar anticancer activity against acute myeloid leukemia cell lines via apoptosis induction and cell cycle arrest.
- PTB was found to inhibit histone deacetylases, leading to increased acetylation of histone H3 and tubulin, as well as upregulation of p21
This document summarizes 16 peer-reviewed articles related to the research of Thomas Ruhland. The articles cover a range of topics including electrochemical grafting of TiO2 photoanodes, new tools for high-throughput organic synthesis, the racemization mechanism of chiral organolithium compounds, the discovery of an antidepressant compound, and the identification of new non-peptidic NK3 receptor antagonists. Thomas Ruhland is an author on several of the articles and his research involved developing new synthetic methods and applying them to medicinal chemistry projects.
The bulbs and aerial parts of Zephyranthes concolor were found to contain six alkaloids: chlidanthine, galanthamine, galanthamine N-oxide, lycorine, galwesine, and epinorgalanthamine. High resolution 1H and 13C NMR spectra were recorded for chlidanthine, which was identified through 2D NMR experiments and X-ray crystallography. Chlidanthine and galanthamine N-oxide showed acetylcholinesterase inhibitory activity, though weaker than galanthamine. The alkaloids also showed poor anti-HIV activity and low cytotoxicity.
This document describes a study that synthesized a new class of tyrosinase inhibitors called azachalcones. Azachalcone derivatives were tested for their ability to inhibit the enzyme tyrosinase, which is involved in melanin biosynthesis. Two compounds that were reduction products of pyridinyl azachalcones strongly inhibited tyrosinase activity and were more potent inhibitors than the positive control kojic acid. Kinetic studies showed that these two compounds act as competitive inhibitors of tyrosinase by binding to the enzyme's active site. This new class of azachalcone inhibitors could potentially be used as depigmenting agents or to prevent browning in foods.
Basic Concepts Of Retrosynthesis (Part1)munirnizami
1. The document discusses the basic concepts of retrosynthetic analysis in organic synthesis. Retrosynthesis is the process of working backward from a target molecule to design synthetic routes using disconnections and functional group interconversions.
2. Key concepts include synthons, which are idealized fragments formed by imagined bond cleavages, and synthetic equivalents, which are actual reagents that can function as those synthons.
3. Effective retrosynthesis requires understanding reaction mechanisms and reliable reactions, as well as considering availability of starting materials and stereochemistry.
1) Molecular simulations were used to analyze the mode of inhibition of three pesticides (baygon, metacrate, and velpar) on firefly luciferase. The simulations revealed that the pesticides share the same binding site in the luciferin pocket of luciferase.
2) Experiments were conducted to determine the toxicities of the three individual pesticides and 15 binary mixtures on firefly luciferase bioluminescence. Concentration addition modeling was able to predict the toxicities of the mixtures based on the molecular simulation results.
3) There was a linear relationship found between the calculated binding free energy of the mixtures from the individual pesticide components, and the median effective concentrations of the mixtures in experiments.
1) A solid-phase method for synthesizing oxazolidinones is described which uses solid-phase activation/cycloelimination (SP/ACE). This involves attaching a 1,2-diol to a polymer-bound sulfonyl chloride, reacting one alcohol with an isocyanate, then cycloelimination to form the oxazolidinone.
2) A variety of oxazolidinones were synthesized in good overall yields using this method by changing the R groups on the isocyanate and diol substrates. Enantiopure oxazolidinones were also prepared using a chiral diol derived from D-mannitol.
3) The azidomethyl groups
Bioisosterism is a strategy used in drug design that involves replacing one chemical group with another that has similar physical or chemical properties. This is done to improve properties like potency, selectivity, toxicity, and pharmacokinetics without significantly changing the chemical structure. Common bioisosteric replacements include replacing hydrogen with fluorine, replacing carboxylic acids with amides or esters, or replacing phenyl rings with heteroaromatic or saturated rings. The application of bioisosterism has been an important concept in medicinal chemistry for nearly 80 years and will continue to play a role in drug discovery and optimization.
This document discusses complexation and protein binding. It defines complex compounds as molecules where some bonds cannot be described by classical valence theory. Complexation is the association of two molecules to form a non-covalently bonded entity with a stoichiometry. Ligands interact with central metal ions or atoms via coordinate bonds to form metal complexes. Protein binding is the formation of drug-protein complexes. Factors affecting protein binding include the drug's physicochemical properties, protein concentration and binding sites, drug interactions, and patient characteristics like age and disease state. Kinetics of protein binding influence drug absorption, distribution, metabolism, and elimination.
This document describes research on the synthesis of anti-1,2-diols using aldehyde α-oxygenation followed by organometallic addition. Contrary to previous reports, the researchers found this method produces anti-diols, not syn-diols. They demonstrated the scope of the reaction using different organometallic reagents and applied it to synthesize stereoisomers of oxylipins from a plant, determining the stereochemistry of two natural products. The synthesis involved aldehyde α-oxygenation, organometallic addition, functional group manipulations and comparisons to natural products to assign stereochemistry.
Three symmetrical and two unsymmetrical Schiff bases were synthesized from o-phenylenediamine and substituted salicylaldehydes. The compounds were characterized using various analytical techniques and their antimicrobial activity was tested against bacteria. The symmetrical compounds showed dependence of activity on substituents as H>NO2>Br, while unsymmetrical compounds exhibited higher activity compared to symmetrical ones. The nitro-substituted unsymmetrical compound showed the best antimicrobial properties.
Synthesis of 2-[{4-(t-amino-1-yl)but-2-yn-1-yl }oxy]-1,3-benzothiazole deriva...iosrphr_editor
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
This document summarizes a study that evaluated a glycopeptide esterification method to better estimate sialylation levels and differentiate sialic acid linkages in monoclonal antibodies by MALDI-TOF mass spectrometry. Glycopeptides isolated from tryptic digests of monoclonal antibodies were ethyl esterified. Esterification neutralized sialic acids and decreased metastable fragmentation, allowing more accurate quantification of sialylation. Esterification patterns also enabled differentiation of α2,3 and α2,6 sialic acid linkages. The method was demonstrated to be fast, simple, and effective for monoclonal antibody glycopeptide analysis.
1) Radical retrosynthesis uses one-electron disconnections to simplify synthesis, avoiding protecting groups, functional group interconversions, and redox steps. This enables more direct and minimal syntheses.
2) Radical cross-coupling reactions allow forming C-C and C-X bonds through hydrogen atom transfer or coupling of radicals with redox-active esters, sulfones, or other species. This provides unique chemoselectivity advantages over polar pathways.
3) Case studies demonstrate strategic benefits of radical cross-coupling for synthesis ideality, efficiency, selectivity, and modularity by opening new retrosynthetic opportunities not accessible through two-electron analysis.
stereochemistry and drug action ; basic introduction about stereochemistry and stereoisomers ; pharmacokinetic and pharmacodynamics concept of stereochemistry ; easson Stedman hypothesis ; stereo selectivity criteria .
Shenzhen Guohui lighting Equipment Co., Ltd Allen huang
LED corn light, highbay and floodlight manufacturer ! top quality with competitive price , 3-5 years warranty , at least 120LM/W , help you save 50-70% energy costs !
Allen Huang
sales Director
Shenzhen Guohui Lighting Equipment Co,.Ltd
Tel: 0755-89728339 Fax:0755-89728319
Mob:+8613714593862 Skype :huanglong266 QQ; 2278051053
E-mail : allen@szguohui.com guohui@szguohui.com
Website : www.guohui-light.com
The document discusses the results of a study on the effects of a new drug on memory and cognitive function in older adults. The double-blind study involved 100 participants aged 65-80 who were given either the drug or a placebo daily for 6 months. Researchers found that those who received the drug performed significantly better on memory and problem-solving tests at the end of the study compared to those who received the placebo.
This document summarizes research from recent issues of the journals Management Science and Information Systems Research. It outlines several major research areas in e-business and lists relevant papers for each area, including dynamic pricing, recommendation systems, marketing, data analytics and forecasting, risk management, auctions, online advertising, and others. The research areas cover topics such as pricing strategies, consumer behavior, advertising, analytics, and more. The document provides an overview of recent influential research across multiple fields in e-business.
The document describes various tools and equipment used in industrial production processes, including welding equipment, cranes, paint equipment, computers, cutting tools, screwdrivers, and parts for buses. Several pieces of equipment are identified for specific uses such as moving large pieces, painting buses, cutting materials, and performing heavy work. The overall document provides a brief listing of industrial tools, machines, and components along with their basic functions.
a Vodafone Ghana reputation study me and my colleagues researched and presented in class @ 2015. we have our background, objectives and goals we hope to achieve at the end of the research.
CMPRO Process Guide: Drawing Parts List - BasicsPSA Inc.
CMPRO is Product Lifecycle Management (PLM) software that manages engineering, configuration, inventory, and product data.
For CMPRO training resources visit www.CMPROficiency.com.
This document discusses legal issues for artists, including copyright, consignment, cooperatives, communication, and contracts. It covers intellectual property rights like copyright, what is and isn't protected, and that ideas aren't protectable. It discusses consignment laws in Tennessee, what constitutes a consignment, and how consignment creates a legal trust between artist and gallery. Cooperatives are defined as artist associations that jointly own and market businesses and accept works from members on consignment. The importance of clear communication and written contracts is emphasized, with standard contract terms provided.
We compare the capital cities of the UK and France in a funny and entertaining way by mixing a few fun facts and concluding who wins. This is not to be taken serious. It is just some entertainment for travellers, sight seeing treasure hunters and other freaks. Brought to you by tresoria.ch
Dr. John Blakemore argues that Australia needs to focus on innovation and technology to drive growth and address its economic challenges. He discusses how innovation saved his eyesight and could help solve other problems. Blakemore advocates for engineers and scientists to think differently and challenge the status quo by applying their skills to issues in other fields to develop new solutions and industries for Australia.
This document describes the efficient synthesis of glaziovianin A (GVA) and related isoflavones starting from readily available plant metabolites. A six-step reaction sequence involving bromination, alkylation, oxidation, condensation, epoxidation, and cyclization produced GVA and various alkoxyphenyl derivatives. Both an in vivo sea urchin embryo assay and screening of human cancer cell lines showed that GVA and some derivatives have antimitotic effects by destabilizing microtubules. Structure-activity relationship studies found that certain substituents, such as a methylenedioxy or trimethoxy group, influenced the compounds' potency. GVA was generally the most active compound, inhibiting cancer cell
Bacteria Induced Cryptic Meroterpenoid Pathway in Pathogenic Aspergillus fumi...Debanjan Chatterjee
The document summarizes a presentation on inducing a cryptic meroterpenoid pathway in the pathogenic fungus Aspergillus fumigatus through co-cultivation with the actinomycete Streptomyces rapamycinicus. Co-cultivation led to the activation of a previously silent polyketide synthase gene cluster and the production of novel prenylated polyketides, including Fumicyclines A. Deletion of the polyketide synthase gene confirmed its involvement in biosynthesis. While co-cultivation induced pathway expression, inhibition of histone acetyltransferase did not, suggesting the bacterium alters fungal epigenetic regulation. Understanding secondary metabolism in A. f
Introduction
Classification
Therapeutic values of peptidomimetics
Design of peptidomimetics by manipulation of amino acids
Modification of peptide backbone
Chemistry of prostaglandins, leukotrienes and thromboxanes
Synthesis, characterization, amdet and docking studies of novel diclofenac de...Alexander Decker
This document discusses the synthesis and characterization of novel diclofenac derivatives containing phenylalanine moieties as selective inhibitors of cyclooxygenase-2 (COX-2). Sixteen novel diclofenac derivatives were synthesized and their structures were confirmed through various analytical techniques. Molecular docking studies predicted that compounds 7, 12 and 16 showed stronger binding with COX-2 than the reference drug diclofenac, making them potential selective COX-2 inhibitors. The binding scores of these compounds were higher than diclofenac when docked into the active site of COX-2.
This document describes a study that investigated the antioxidant compounds in Levisticum officinale (lovage). Ethyl acetate extracts of the plant's roots showed the highest antioxidant activity. Three active compounds - bergapten, ferulic acid, and vanillin - were isolated from the extract through column chromatography and identified using NMR spectroscopy. Bergapten and ferulic acid exhibited potent antioxidant effects in DPPH radical scavenging assays, similar to the positive control BHT. This study identified these compounds as responsible for the antioxidant properties found in some fractions of L. officinale root extracts. Further research is needed to evaluate other active fractions.
COMPARISON FREE ENERGY BINDING SITES NEURAMINIDASEijabjournal
Neuraminidase (NA) is the essential surface glycoprotein of the influenza virus. High- affinity neuraminidase inhibitors have been designed that interact only with the conserved active site and binding site residues. The neuraminidase (NA) of influenza virus is the target of anti – flu drug.for treatment of this
disease a thorough knowledge of neuraminidase protein is essential in order to produce potent drugs to suppress this enzyme..Drug design is by QSAR and docking methods, so we need a complete knowledge of receptor ligand, target site and binding site. This paper, using bioinformatics, Molecular Dynamics, Monte carlo and studied binding site NA enzyme in 310K temperature and different dielectrics (1, 78.39 and
32.63) for the best drug designing. We measured the potential energy of amino acids binding to the drug.Molecular Mechanics, Molecular Dynamic and Nanobiological have done a great assistance in drug designing.
This document summarizes the design and testing of a bisubstrate inhibitor for the insulin receptor tyrosine kinase (IRK). Researchers designed a compound that links ATPγS to a peptide substrate analog via a two-carbon spacer, setting the distance between the nucleophilic atom and phosphoryl group to mimic a dissociative transition state as suggested by previous studies of IRK's mechanism. Testing found this compound to be a potent and selective competitive inhibitor of IRK, with a Ki of 370 nM, making it the most potent inhibitor reported for this important signaling enzyme. A crystal structure confirmed the inhibitor bound as designed and validated the mechanism-inspired approach.
1) The document describes the design and synthesis of new (bis)ureidopropyl and (bis)thioureidopropyl diamine compounds as inhibitors of the histone demethylase LSD1.
2) Key compounds featured 3-5-3 and 3-6-3 carbon backbone architectures. Several compounds displayed single-digit micromolar IC50 values against recombinant LSD1 in vitro.
3) Compound 6d showed low micromolar cell viability IC50 values against lung and breast cancer cell lines. It also increased mRNA expression of silenced tumor suppressor genes in lung cancer cells.
A STUDY TO EVALUATE THE IN VITRO ANTIMICROBIAL ACTIVITY AND ANTIANDROGENIC E...Dr. Pradeep mitharwal
The present paper deals with synthesis and characterization
of some new chromium (III) Schiff base complexes using microwave irradiation
technique as well as conventional heating. The S∩N donor benzothiazolines, 1-
(2-furanyl) ethanone benzothiazoline (Bzt1N
∩
SH), 1-(2-thienyl) ethanone
benzothiazoline (Bzt2N
∩
SH) and 1-(2-pyridyl) ethanone benzothiazoline
(Bzt3N
∩
SH) were prepared by the condensation of ortho-aminothiophenol with
respective ketones in ethanol.
We investigated the gas‐phase fragmentation reactions of a series of 2‐aroylbenzofuran derivatives
by electrospray ionization tandem mass spectrometry (ESI‐MS/MS). The most intense fragment
ions were the acylium ions m/z 105 and [M+H–C6H6]+, which originated directly from the
precursor ion as a result of 2 competitive hydrogen rearrangements. Eliminations of CO and CO2
from [M+H–C6H6]+ were also common fragmentation processes to all the analyzed compounds.
In addition, eliminations of the radicals •Br and •Cl were diagnostic for halogen atoms at aromatic
ring A, whereas eliminations of •CH3 and CH2O were useful to identify the methoxyl group
attached to this same ring. We used thermochemical data, obtained at the B3LYP/6‐31+G(d) level
of theory, to rationalize the fragmentation pathways and to elucidate the formation of E, which
involved simultaneous elimination of 2 CO molecules from B.
Objective(s):
Nanotechnology and nanoparticles are increasingly recognized for their potential applications in aerospace engineering, nanoelectronics, and environmental remediation, medicine and consumer products. More importantly is the potential for the application of silver nanoparticles (Ag NPs) in the treatment of diseases that require maintenance of circulating drug concentration or targeting of specific cells or organs the aim of this study was to investigate the possible protective role of Ag NP antioxidative biomarkers in rats. Ag NPs are used to investigate the potential risks for the environment and health.
Materials and Methods:
Rats received Ag NP, 5, 50, 250 and 500 mg/kg/day IP. After two week of treatment, the activity of enzymatic scavengers such as glutathione peroxidase (GPx), superoxide dismutase (SOD) and total antioxidant capacity (TAC) of blood samples were measured.
Results:
Ag NP in 5, 50, 250 and 500 mg/kg reduced activities of CAT, SOD and increased TAC in plasma.
Conclusion:
In this study, Ag NP with 500mg/kg induced activities of CAT, SOD and decreased TAC. It is concluded that antioxidative properties of Ag NP is dose dependent.
Exploring N-Ferrocenylmethylaniline Derivatives as Potent Anti-Breast Cancer ...Trustlife
Exploring N-Ferrocenylmethylaniline Derivatives as Potent Anti-Breast Cancer Agents: Insights from Computational Chemistry, Pharmacokinetics, and QSAR Analysis
Austin Journal of Bioorganic & Organic Chemistry is a peer reviewed, open acc...Austin Publishing Group
Austin Journal of Bioorganic & Organic Chemistry is a peer reviewed, open access journal publishes manuscripts in the following areas but not limited to structures, synthesis, kinetics, organic synthesis, physical organic chemistry, supramolecular chemistry and chemical biology.
Austin Journal of Bioorganic & Organic Chemistry accepts original research articles, review articles, commentaries, Letters, perspectives, and rapid communication on all the aspects of Bioorganic & Organic Chemistry.
Voss et al. - 2006 - Identification and characterization of riproximin,Cristina Voss
1. Researchers purified and characterized a new type II ribosome-inactivating protein called riproximin from the plant Ximenia americana.
2. Riproximin was found to potently inhibit protein synthesis and cancer cell growth in vitro with picomolar IC50 values, and inhibit tumor growth in vivo after intraperitoneal or oral administration in a rat model.
3. The researchers identified the riproximin protein through mass spectrometry and cDNA sequencing. Molecular modeling showed riproximin has structural similarity to other toxic type II ribosome-inactivating proteins and an active site for its RNA N-glycosidase activity.
Proteome-wide covalent ligand discovery in native biological systemsMegha Majumder
The document describes a new method for finding drug candidates that bind to specific proteins called isoTOP-ABPP. It involves applying small molecule fragments that covalently bind to cysteine amino acids on proteins. This allows researchers to detect which proteins the fragments bind to. They tested a library of these fragments on cancer cell proteins and found they bound to over 750 cysteines on more than 600 proteins, including some previously considered undruggable. Further experiments showed some fragments could selectively target and inhibit certain proteins like IDH1/2 and label inactive pro-forms of proteins like caspase-8, but not the active forms.
This document describes a study investigating potential inhibitors of human calcium–calmodulin dependent protein kinase IV (CAMKIV) containing a pyrimidine scaffold. Through molecular docking and fluorescence binding studies, three pyrimidine-substituted compounds (molecules 1-3) were identified as having high binding affinity for CAMKIV. Molecule 3 showed the highest binding affinity with a binding constant of 2.2 × 108 M−1. The three compounds were nontoxic to cells and molecule 3 had the lowest IC50 value, indicating it inhibits cell proliferation the most. This study provides insights for developing improved pyrimidine-based compounds as potential therapeutic agents for cancer and neurodegenerative diseases by targeting CAMKIV
1) Novel compounds called O,O-diethyl 1-benzamido-2,2-biscarbamoylethanephosphonates were synthesized as substrates for HIV-1 protease (PR) to exploit activation of the phosphonate group.
2) One compound, O,O-diethyl 1-benzamido-2,2-bis[(1S)-N-(1-benzyl-2-hydroxyethyl)carbamoyl]ethanephosphonate, showed moderate anti-HIV activity in vitro. Its depsipeptide analogue inhibited HIV-1 PR with an IC50 of 31 μM.
3) The phosphonate group of these compounds was designed
1) Four flavonoids (tiliroside, 3-methoxyquercetin, quercitrin, and quercetin) were isolated from Agrimonia pilosa ledeb and showed inhibitory effects on acetylcholinesterase (AChE).
2) Quercetin showed twice the AChE inhibitory activity of dehydroevodiamine, a known AChE inhibitor.
3) The isolation of these compounds from A. pilosa ledeb represents the first report of AChE inhibitory activity of components from this plant species.
1. pubs.acs.org/jmc Published on Web 10/27/2010 r 2010 American Chemical Society
8202 J. Med. Chem. 2010, 53, 8202–8206
DOI: 10.1021/jm1009567
Endoperoxide Carbonyl Falcipain 2/3 Inhibitor Hybrids: Toward Combination
Chemotherapy of Malaria through a Single Chemical Entity
Peter Gibbons,†
Edite Verissimo,‡
Nuna C. Araujo,‡
Victoria Barton,†
Gemma L. Nixon,§
Richard K. Amewu,†
James Chadwick,†,
)
Paul A. Stocks,§
Giancarlo A. Biagini,§
Abhishek Srivastava,§
Philip J. Rosenthal,^
Jiri Gut,^
Rita C. Guedes,#
Rui Moreira,#
Raman Sharma,†,§
Neil Berry,†
M. Lurdes S. Cristiano,‡
Alison E. Shone,§
Stephen A. Ward,§
and Paul M. O’Neill*,†,
)
†
Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, U.K., ‡
Department of Chemistry, Biochemistry and Pharmacy, and
CCMAR, University of the Algarve, Campus de Gambelas, Faro, 8005-039, Portugal, §
Liverpool School of Tropical Medicine, Pembroke Place,
Liverpool, L3 5QA, U.K.,
)
MRC Centre for Drug Safety Science, Department of Pharmacology, University of Liverpool, Liverpool,
L69 3GE, U.K., ^
Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California 94143-0811,
United States , and #
iMed.UL, Faculty of Pharmacy, University of Lisbon, Av Prof. Gama Pinto, 1649-003, Portugal
Received July 27, 2010
We extend our approach of combination chemotherapy through a single prodrug entity (O’Neill et al.
Angew. Chem., Int. Ed. 2004, 43, 4193) by using a 1,2,4-trioxolane as a protease inhibitor carbonyl-
masking group. These molecules are designed to target the malaria parasite through two independent
mechanisms of action: iron(II) decomposition releases the carbonyl protease inhibitor and potentially
cytotoxic C-radical species in tandem. Using a proposed target “heme”, we also demonstrate heme
alkylation/carbonyl inhibitor release and quantitatively measure endoperoxide turnover in parasitized
red blood cells.
Introduction
As a tractable solution to Plasmodium falciparum resistance
development,1
we have developed a novel protease inhibitor
peroxide hybrid strategy that encapsulates and refines the
concept of combination chemotherapy. Our approach is based
on the ability of Fe(II) or heme to selectively cleave the peroxide
bridge of the endoperoxide class of drug, a process that appears
to be restricted to the malaria parasite. We have designed
synthetic routes to produce antimalarial drug hybrids that,
as a function of heme (or ferrous iron dependent) peroxide
cleavage, will liberate not only free radicals (proposed arte-
misinin type of action)2
but also a second antimalarial drug
with an independent mechanism of action.
Although the specific mechanism of action of the endoper-
oxide antimalarials remains controversial,3-5
we have based
our hybrid strategy on previous findings using biomimetic
Fe(II) chemistry and electron paramagneticresonance(EPRa
)
spectroscopy. We have provided evidence that the Roche anti-
malarial arteflene releases a potentially toxic carbon centered
radical in tandem with an electrophilic enone.6
On the basis of
a mechanistic understanding of this process, we developed
chemistry for the preparation of a new series of endoperoxide
cysteine protease inhibitor (ECPI (1a)) prodrugs, compounds
that have the capacitytoselectively delivertwo toxicentitiesto
the malaria parasite. Specifically, we demonstrated that under
ferrous mediated conditions, our prototype antimalarials (1a)
degrade by a designed cascade to produce in a concomitant
fashion a potentially toxic carbon radical (2a) and a chalcone
molecule (2b), an entity capable of inhibiting the malaria
trophozoite cysteine protease falcipain 2.7
Strategy
The selective parasite reductive cleavage of the endoper-
oxide prodrug (e.g., 1a) to an enone system and a secondary
C-centered radical might suggest that this approach is rela-
tively limited in the type of inhibitor that can be embedded
within the prodrug. On the contrary, mechanistic studies by
Vennerstrom on the ferrous mediated decompositions of the
1,2,4-trioxolane pharmacophore have revealed that this hetero-
cycle also readily degrades to carbonyl species in tandem with
free radical production (Figure 2A).8
With this knowledge
and as a paradigm for a potentially generic approach to com-
bination chemotherapy, we have focused on peroxides incor-
porating novel peptidic cysteine protease (falcipain 2/3) inhib-
itors, compounds with antimalarial effects at the level of the
parasite digestive vacuole. Falcipain 2 has been selected as
a target, since we have a good working knowledge of the
biochemistry and structure-activity relationships (SAR) for
carbonyl-based inhibitors of this key protease enzyme.9
A key consideration for this strategy is the interaction of the
two components combined within the single chemical entity.
Combining artemisinin with a chalcone derivative indepen-
dently as an artemisinincombination therapy (ACT) results in
synergistic or additive interactions suggesting that endoper-
oxides and chalcones can be used together effectively.10
Thus,
the prodrug approach previously explored (Figure 1) has
significant advantages over the use of either drug in combination
or alone, since it allows selective drug delivery (i.e., metabol-
ically stable) to the parasite food vacuole reducing toxicity to
*To whom correspondence should be addressed. Phone: 0151 794
3553. Fax: þ44 (0)151 794 3588. E-mail: pmoneill@liverpool.ac.uk.
a
Abbreviations:ALLN,calpain inhibitor I, N-acetyl-Leu-Leu-Norleu-al;
ECPI, endoperoxide cysteine protease inhibitor; ACT, artemisinin
combination therapy; SAR, structure-activity relationship; CP, cysteine
protease;EPR,electron paramagneticresonance;MRM,multiplereaction
monitoring.
2. Brief Article Journal of Medicinal Chemistry, 2010, Vol. 53, No. 22 8203
the host cell and its dual mechanism of action should reduce
the chance of parasite resistance acquisition.
In line with the above discussion, in the case of peptidic
carbonyl based cysteine protease inhibitors (e.g., calpain
inhibitor I, N-acetyl-Leu-Leu-Norleu-al (ALLN)) we have
demonstrated by isobologram analysis that the interaction
with artemisinins and synthetic 1,2,4-trioxanes are additive
and not antagonistic. With this in mind, for the purposes
of comparison, two subsets of carbonyl-based inhibitor were
targeted; the carbonyl containing peptides (3a-g) and the
1,2,4-trioxolane prodrugs (4a-f) (Figure 2B).
Chemistry Experimental
The synthesis of target aldehyde inhibitors is presented in
Scheme1A.Briefly,reductionofdipeptideesters5aand5bfollowed
bySwernoxidationofalcoholsof6aand6bprovided aldehydes 3,
3a, and 3b. In studies by Veber on potent low nanomolar peptidic
cathepsin K inhibitors it was demonstrated that alkoxymethyl
ketones areconsiderably morestablethan their aldehydecounter-
parts, and for this reason we also included the cysteine protease
(CP) inhibitors 3c-f as targets (Figure 2).11
Docking studies with the falcipain 2 crystal structure (PDB code
2OUL, 2.20 A˚ )12
were performed for the aldehyde and ketone
based inhibitors, and docking poses are presented in Figure 3.
Each ligand was energy-minimized and then subjected to 10 000
docking runs. The top 10 ranking solutions (i.e., those with the
highest fitness score13
) were visually analyzed for (i) the distance
between the potentially reactive carbon atoms (i.e., ketone/alde-
hyde carbonyl and CH2OR) and the sulfur atom of the catalytic
Cys42 residue, (ii) hydrogen bond interactions in the proposed
oxy anion hole formed by the residues Gln36, His174, and Cys42,
and (iii) hydrophobic interactions between the ligand and non-
polar regions of the enzyme surface. Energy minimized structures
place the carbonyl warhead of the inhibitor in the vicinity of
Cys42 residue (<4 A˚ ) and the gold scores for 3c-f encouraged
ketone inhibitor synthesis.
Peptides 3c-g were prepared in good overall yields using pre-
viously reported standard peptide coupling techniques. The syn-
thesis proceeded with hydrolysis of dipeptides 5a and 5c to acids
7a and 7b followed by Weinreb amide formation and subsequent
Grignard addition chemistry to deliver 3c-f (Scheme 1B).14
Followingoptimizationstudiesthetargetprodrugs(4a-f) werepro-
ducedbyGriesbaumco-ozonolysisusingO-methyl2-adamantanone
oxime/O3 and the prodrugs were purified by HPLC as an insepa-
rable mixture of 1:1 diastereomers.15
Discussion
Table1listsenzymeinhibitorydataofallcompoundsprepared
against recombinant falcipains 2 and 3 and the antimalarial
activity against 3D7 malaria parasite strain.16
It is immedi-
ately clear that the aldehydes 3a and 3b are potent and selective
inhibitors of falcipain 2 with low nanomolar activity. In the
keto series only R-phenoxy analogue 3g expresses nanomolar
activity against falcipains 2 and 3. As noted previously, 3a and
3b also express low nanomolar antimalarial activity versus the
3D7 strain of Plasmodium falciparum; apart from 3g, alkoxy
ketone inhibitors had low activity against both enzymes
(2-21 uM). This is surprising given the fact that (a) these
molecules contain the optimalresiduesLeu andhomophe/Phe
within the structure of the inhibitor and (b) the docking
studies performed with FP2 suggested a good enzyme fit for
this series. The modest activity for 3c-g suggests that the
reactivity of the R-alkoxy group, when compared with the
reactive aldehyde in 3a and 3b, is insufficient to achieve efficient
inactivation of Cys 42 through the usual 1,2-addition process.
The most potent endoperoxides from the series are the alde-
hyde prodrugs 4, 4a, and 4b and ketone prodrugs 4c and 4e.
Trioxolane 4b is active in the low nanomolar region (35 nM)
with 4a active at 55 nM versus the 3D7 strain of Plasmodium
falciparum. The activities of the parent prodrugs 4a and 4b
were significantly less against the recombinant enzyme
(>400 nM). Since there is more than a 400-fold difference
between the inhibitory potency for aldehyde 3a and endoper-
oxide 4a versus falcipain 2, the fact that these molecules express
similar activity versus cultured parasites (27 nM versus 55 nM)
indicates that activation and inhibitor release are contributing
to the observed whole cell parasite growth inhibition for 4a.
That 4c-f express moderate antimalarial activity demon-
strates that molecules containing the privileged 1,2,4-trioxo-
lane heterocycle do not necessarily have potent antimalarial
properties. The fact that 4c-f are not as active as some spiro-
cyclohexyl systems may be again a stability issue (or more
likely, as suggested later, the alkoxy group could be hindering
Figure 1. Designedferrousmediateddegradationofchalconeprodrug.
Figure 2. (A) Fragmentation of endoperoxide to secondary carbon
centred radical species and protease inhibitor. (B) Carbonyl based
falcipain 2/3 inhibitors: Cbz=benzyloxycarbonyl; Mu=morpholine
urea.
3. 8204 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 22 Gibbons et al.
the approach of reducing iron to the endoperoxide-bridge in
this trioxolane).
Initial mechanistic studies conducted with trioxolane model
compound 4g (IC50=100 nM vs 3D7) indicated the feasi-
bility of our approach, since this aldehyde prodrug was
efficiently turned over to the requisite aldehyde as shown in
Scheme 2 in addition to two distinct carbon centered radical
species. The expected adduct 10a was obtained in 20% yield in
combination with 10d. We propose that 10d is derived from
the benzylic C-radical intermediate produced itself by a 1,5-H-
shift of the initially formed oxyl centered radical as shown in
Scheme 2.
With this result in hand we turned to peptide aldehyde
prodrug analogue 3. Scheme 3 provides data on the conver-
sion of selected trioxolane 4 in the presence of ferrous bromide
and with heme. For 4, using FeBr2, we were able to character-
ize a secondary carbon centered radical spin-trapped adduct
Figure 3. Docking poses of aldehydes 3a (A), 3b (B), and 3g (C) in the active site of falcipain 2, obtained from PDB 2OUL. Figures were
prepared using Pymol.
Table 1. Enzyme Inhibition (Falcipain 2/3) and Antimalarial Activity
of Inhibitors and ECPI Prodrugs
IC50 (nM ( SD)
analogue
recombinant
falcipain 2
recombinant
falcipain 3
IC50 (nM)
Plasmodium
falciparum 3D7
3a 1.4 ( 0.2 198.9 ( 1.06 27.1
3b 16.3 ( 0.9 214.6 ( 11.3 9.3
3c 7149.5 ( 245 5597 ( 1563.7 >10000
3d 1966 ( 254 8613 ( 913.5 >10000
3e 2048.5 ( 14.8 853 ( 149 >10000
3f 1961 ( 247 21600 ( 198 >10000
3g 437.7 ( 47.7 222 ( 77.8 310
4a 425.3 ( 34.5 947 ( 133 55.5
4b 510.23 ( 25.2 332 ( 18.1 35.3
4c <11500 ( 452 <19780 ( 3903 582
4d 1200 ( 1230 44155 ( 7332 2564
4e <8668 ( 501 <24215 ( 5239 572
4f <8583 ( 794 >25000 ND
artemisinin NA NA 12.5
Scheme 1. Synthesis of 1,2,4-Trioxolane Prodrugsa
a
Part A: (a) CaCl2, NaBH4, MeOH, -5 °C, 2 h; (b) (COCl)2, DMSO, Et3N, CH2Cl2, 0 °C to room temp, 3 h; (c) O3, pentane/CH2Cl2 (4:1), carbonyl
protease inhibitor. Part B: (d) 2 N NaOH, MeOH, room temp, 16 h; (e) MeONHMe 3 HCl, HOBt, EDAC, DMAP, DIEA, CH2Cl2, 0°C, 3 h; (f) Mg,
HgCl2, ROCH2Cl, THF, -25 °C, 1.5 h.
Scheme 2. Degradation of 1,2,4-Trioxolane Aldehyde Model
4. Brief Article Journal of Medicinal Chemistry, 2010, Vol. 53, No. 22 8205
9a (quantitative yield) along with lactone 9b (see mechanism
involving a single electron transfer (SET)) from ferric iron and
oxidation of the radical to a carbocation with subsequent ring
closure. Treatment of trioxolane 4 with Fe(II) in the absence
of 4-oxo TEMPO provided a 96% yield of the aldehyde along
with 30% of the lactone 9b. The corresponding reaction with
heme (generated from hemin chloride and sodium dithionite)
also led to cleavage of the prodrug to the aldehyde in 54%
yield in tandem with heme alkylated adduct 9c which was
characterized by LC/MS.
In terms of carbonyl release the reactivity of the corre-
sponding R-alkoxy ketone inhibitor 4e was much slower with
62% turnover depending on the iron source used.It was consi-
dered that the alkoxy group could be hindering the approach
of reducing iron to the endoperoxide bridge in this prodrug.
In order to obtain definitive proof of inhibitor release within
the living malaria parasite two experiments were performed in
late ring/early trophozoites.Parasiteswereexposedto1μMor
100 nM prodrug 4. After this time, the media were removed
via centrifugation (2000g  5 min), and red blood cells were
lysed by the addition of 5 mL of acetonitrile/methanol/water
(40:40:20). The lysed material was triturated through a pipet
and the lysis solution separated by centrifugation (3000g Â
5 min). The lysis solution was then analyzed via LC/MS/MS
(Supporting Information). As a control, nonparasitised red
blood cells were treated in exactly the same manner. Figure 4
shows the representative chromatograms of 3 (Figure 4A) and
4 (Figure 4B) obtained after the analysis of 20 μL aliquot of
100nMincubationof4(incubationof20μLaliquotof100nM)
with chloroquine-sensitive Plasmodium falciparum (3D7) para-
sitized red blood cells for 4 h. It was found that after 4 h of
incubation 4 was converted to 54 nM 3 (54% yield) with only
minor amounts of the trioxolane remaining (1.5 nM detected
by LC/MS/MS). Notably, in uninfected erythrocytes, turn-
over to the aldehyde 3 was considerably lower.
Conclusion
We have completed the synthesis and assessment of car-
bonyl based protease inhibitors and their endoperoxidehybrids.
Studies on the ferrous mediated decomposition of these molec-
ules have definitively proven that these systems degrade by
carbonyl inhibitor formation in tandem with C-radical for-
mation. In studies with a viable parasitic target we have demon-
strated efficient heme alkylation with concomitant carbonyl
inhibitor release. Furthermore, using LC/MS/MS, we have
described for the first time a quantitative intraparasitic esti-
mation of endoperoxide turnover in 3D7 parasites following
a 4 h exposure to trophozoites. One potential caveat to this
Figure 4. Representative chromatograms of 3 and 4 obtained after the analysis of 20 μL aliquot of 100 nM incubation of 4 with 3D7 malaria
parasites. Ion current intensities and multiple reaction monitoring (MRM) transitions are shown in each chromatogram.
Scheme 3. Ferrous Mediated Fragmentation of Prodrug 4 (R=Cbz-Leu) and Spin Trapping with 4-Oxo TEMPOa
a
Reactions were performed at 35 °C under nitrogen. Solvent for FeBr2 is ACN/DCM (1:1). Solvent for heme is ACN/H2O (3:1).
5. 8206 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 22 Gibbons et al.
approach with the 1,2,4-trioxolane heterocycle is the capacity
of this system to undergo Hock cleavage under mildly acidic
conditions (see Supporting Information Figure S4). While our
in vitro studies with iron(II) species definitively prove C-radical
formation in tandem with carbonyl release, we cannot rule out
that this process is occurring within the acidic digestive
vacuole of Plasmodium falciparum. A Hock mediated release
of the inhibitor, while ensuring efficient delivery, would not
provide the desired dual targeting effect. This competing
degradation pathway could explain, in part, the lower than
expected antimalarial activity for 4a and 4b. Further work
will focus on the optimization of the endoperoxide carbonyl
masking group in terms of tuning the reactivity to achieve
selective and controlled drug release within the parasite target
while maintaining appropriate pharmacokinetic properties.
Acknowledgment. This work was supported by grants from
the BBSRC (U.K.) (P.M.O.N., V.B., S.A.W.; Grants BB/
C006321/1, BBS/B/05508, BBS/Q/Q/2004/06032, and BBS/
S/P/2003/10353) and by the European Commission (Antimal
FP6 Malaria Drugs Initiative).
Supporting Information Available: Experimental details. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Note Added after ASAP Publication. The version of this
paper that was published ASAP October 27, 2010, was missing
author Nuna C. Araujo from the author list. The revised
version was published October 29, 2010.
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