Sulfonamides are a class of antimicrobial drugs that were the first widely used antibiotics. They work by interfering with the synthesis of folic acid in bacteria, which is essential for their growth. Key points discussed include the mechanism of action, structure-activity relationships, classification, side effects and synthesis of important sulfonamide drugs like sulfadiazine and sulfamethoxazole. The document provides detailed information on the medicinal chemistry of sulfonamides.
1. Chemotherapy uses cytotoxic drugs to kill cancer cells or stop their growth by interfering with cell division. It is indicated when cancer has spread and cannot be treated with surgery or radiation alone.
2. There are several classes of chemotherapeutic drugs including antimetabolites, alkylating agents, antibiotics, and microtubule inhibitors. Antimetabolites interfere with DNA and RNA production. Alkylating agents damage DNA to cause cell death. Antibiotics and microtubule inhibitors affect DNA/RNA and microtubule formation.
3. Side effects of chemotherapy can include bone marrow suppression, nausea, vomiting, alopecia, and organ-specific toxicities depending on the drug. Cancer cells can also
Antineoplastic agents can be classified as cytotoxic drugs, hormones, or miscellaneous agents. Cytotoxic drugs include alkylating agents, antimetabolites, plant derivatives, and antibiotics. They work by directly damaging DNA or interfering with cell division and metabolism. Combination therapy is more effective than single agents to increase response rates and decrease resistance development.
This document discusses pharmacological agents that target DNA replication. It begins by outlining the two main mechanisms by which these drugs act: direct interference with DNA replication processes and inducing checkpoint responses. It then describes several classes of drugs in more detail, including nucleotide triphosphate inhibitors like methotrexate and 5-fluorouracil, purine antimetabolites like 6-mercaptopurine and 6-thioguanine, and hydroxyurea. It also discusses chain elongation inhibitors such as cytosine arabinoside and gemcitabine. These drugs inhibit DNA synthesis and are used to treat rapidly dividing cancers, though they can also harm rapidly dividing normal cells.
The document provides an overview of antibiotics and their mechanisms of action. It focuses on two main classes: sulfonamides and beta-lactams (penicillins and cephalosporins). Sulfonamides work by inhibiting the bacterial enzyme dihydropteroate synthetase, blocking the synthesis of the essential co-factor tetrahydrofolate. Beta-lactams like penicillins inhibit the final cross-linking step in bacterial cell wall synthesis by irreversibly binding transpeptidase enzymes via their electrophilic beta-lactam rings. Resistance issues with both drug classes are also discussed.
Alkylating agents and antimetabolites are two classes of chemotherapy drugs. Alkylating agents work by binding to DNA and RNA, causing crosslinking or breaks that prevent replication. The main types are nitrogen mustards, alkyl sulphonates, nitrosoureas, and thiazines. Antimetabolites mimic normal metabolites and inhibit DNA or RNA synthesis by becoming incorporated. Major types are folate antagonists like methotrexate, pyrimidine analogs like 5-fluorouracil, and purine analogs like mercaptopurine. Both classes cause bone marrow suppression and gastrointestinal toxicity, and resistance can develop through drug inactivation or changes to drug targets.
This document discusses sulfonamides and their mechanism of action as folic acid antagonists. It provides details on:
1. How sulfonamides inhibit the synthesis of folic acid by competing with para-aminobenzoic acid for the enzyme dihydropteroate synthetase.
2. The classification, antibacterial spectrum, mechanisms of resistance and uses of various sulfonamides like sulfamethoxazole.
3. How trimethoprim inhibits the enzyme dihydrofolate reductase, preventing the conversion of dihydrofolate to tetrahydrofolate. When combined with sulfamethoxazole as co-trimoxazole it has a synergistic
1. Chemotherapy uses cytotoxic drugs to kill cancer cells or stop their growth by interfering with cell division. It is indicated when cancer has spread and cannot be treated with surgery or radiation alone.
2. There are several classes of chemotherapeutic drugs including antimetabolites, alkylating agents, antibiotics, and microtubule inhibitors. Antimetabolites interfere with DNA and RNA production. Alkylating agents damage DNA to cause cell death. Antibiotics and microtubule inhibitors affect DNA/RNA and microtubule formation.
3. Side effects of chemotherapy can include bone marrow suppression, nausea, vomiting, alopecia, and organ-specific toxicities depending on the drug. Cancer cells can also
Antineoplastic agents can be classified as cytotoxic drugs, hormones, or miscellaneous agents. Cytotoxic drugs include alkylating agents, antimetabolites, plant derivatives, and antibiotics. They work by directly damaging DNA or interfering with cell division and metabolism. Combination therapy is more effective than single agents to increase response rates and decrease resistance development.
This document discusses pharmacological agents that target DNA replication. It begins by outlining the two main mechanisms by which these drugs act: direct interference with DNA replication processes and inducing checkpoint responses. It then describes several classes of drugs in more detail, including nucleotide triphosphate inhibitors like methotrexate and 5-fluorouracil, purine antimetabolites like 6-mercaptopurine and 6-thioguanine, and hydroxyurea. It also discusses chain elongation inhibitors such as cytosine arabinoside and gemcitabine. These drugs inhibit DNA synthesis and are used to treat rapidly dividing cancers, though they can also harm rapidly dividing normal cells.
The document provides an overview of antibiotics and their mechanisms of action. It focuses on two main classes: sulfonamides and beta-lactams (penicillins and cephalosporins). Sulfonamides work by inhibiting the bacterial enzyme dihydropteroate synthetase, blocking the synthesis of the essential co-factor tetrahydrofolate. Beta-lactams like penicillins inhibit the final cross-linking step in bacterial cell wall synthesis by irreversibly binding transpeptidase enzymes via their electrophilic beta-lactam rings. Resistance issues with both drug classes are also discussed.
Alkylating agents and antimetabolites are two classes of chemotherapy drugs. Alkylating agents work by binding to DNA and RNA, causing crosslinking or breaks that prevent replication. The main types are nitrogen mustards, alkyl sulphonates, nitrosoureas, and thiazines. Antimetabolites mimic normal metabolites and inhibit DNA or RNA synthesis by becoming incorporated. Major types are folate antagonists like methotrexate, pyrimidine analogs like 5-fluorouracil, and purine analogs like mercaptopurine. Both classes cause bone marrow suppression and gastrointestinal toxicity, and resistance can develop through drug inactivation or changes to drug targets.
This document discusses sulfonamides and their mechanism of action as folic acid antagonists. It provides details on:
1. How sulfonamides inhibit the synthesis of folic acid by competing with para-aminobenzoic acid for the enzyme dihydropteroate synthetase.
2. The classification, antibacterial spectrum, mechanisms of resistance and uses of various sulfonamides like sulfamethoxazole.
3. How trimethoprim inhibits the enzyme dihydrofolate reductase, preventing the conversion of dihydrofolate to tetrahydrofolate. When combined with sulfamethoxazole as co-trimoxazole it has a synergistic
This document summarizes a seminar presentation on antineoplastic agents. It defines antineoplastic agents as those used to prevent abnormal or uncontrolled cell growth, also known as anticancer agents. The document classifies antineoplastic agents into seven categories - alkylating agents, antimetabolites, plant products, antibiotics, hormones, immunotherapy agents, and miscellaneous agents. For each category, examples are provided and brief descriptions of mechanisms of action and uses. Syntheses of cyclophosphamide and chlorambucil are also outlined.
This document provides a classification and overview of various anti-neoplastic or anticancer drugs. It discusses four main classes: 1) alkylating agents such as cisplatin and cyclophosphamide, 2) antimetabolites including methotrexate and fluorouracil, 3) natural products including vincristine and paclitaxel, and 4) hormones and antagonists like tamoxifen. It then provides more detailed information about the mechanisms and structure-activity relationships of selected drugs, including methotrexate, mercapturine, and tamoxifen.
Plant responses to oxidative stress can cause physiological damage at the lipid, protein, and DNA levels. Physiologically, lipid peroxidation disrupts cell membranes, protein oxidation alters structure and function, and DNA oxidation causes mutations. Biochemically, plants have developed defense mechanisms including superoxide dismutase, catalase, peroxidase, and glutathione to neutralize reactive oxygen species. Glutathione functions in redox reactions and membrane stabilization. Plants also produce antioxidants like carotenoids to counteract oxidative stress and protect cellular components from free radical damage.
Secondary metabolites and abiotic stress-1.pptx66AreejFatima
Secondary metabolites are compounds produced by plants that are not essential for basic plant functions but help plants adapt to environmental stresses. They include phenolic compounds, alkaloids, and terpenes. The document discusses how abiotic stresses like drought, salinity, and temperature affect plant physiology and metabolism. It provides examples of how the secondary metabolite glutathione can help mitigate the effects of salt stress in pea plants by improving factors like chlorophyll content, photosynthesis, and proline levels. The role of secondary metabolites in helping plants tolerate abiotic stress conditions is explored.
Antimetabolites are structurally similar to normal cell compounds and interfere with purine or pyrimidine synthesis or incorporation into DNA/RNA. Common antimetabolites include methotrexate, 6-mercaptopurine, fludarabine, cladribine, 5-fluorouracil, capecitabine, cytarabine, and azacitidine. They are cell cycle specific and used to treat cancers like leukemia, lymphoma, lung cancer, and breast cancer. Common side effects include nausea, vomiting, diarrhea, myelosuppression, and renal toxicity.
Chemical conversion of a substance mediated by living organisms or enzymes
Can result in DETOXIFICATION and BIOACTIVATION
Vital to survive
Key in defense mechanism
In this section, we describe folate antagonists and most of the slides are cited from:
1- Lippincott's Illustrated Pharmacology
2- KD Triphati Pharmacology
3- Basic Katzung Pharmacology
Malaria vaccines cum antimalaria drugs, by bdollarbernard bahaah
This presentation slides give an upto date information on antimalaria drugs and vaccines. It can be used for academic purpose or some other purpose. It highlights some of the successes and potentials of antimalaria drugs.
This document was prepared by Afifa Binta Saifuddin and her group members for the assignment purpose for Department of Pharmacy, East West University, Bangladesh. Uploaded by Tousif Azmain.
The impurities in pharmaceuticals are unwanted chemicals that remain with the active pharmaceutical ingredients
(APIs) or develop during formulation or upon aging of both API and formulation.
This document outlines lectures from a pharmacology course on antibiotics that inhibit cell wall synthesis, protein synthesis, and nucleic acid synthesis. The lectures cover penicillins, cephalosporins, aminoglycosides, sulfonamides, trimethoprim, tetracyclines, macrolides, and chloramphenicol. For each class of antibiotics, the lectures aim to describe their mechanism of action, pharmacokinetics, clinical uses, and adverse effects. The goal is for students to understand how different classes of antibiotics work and their proper use in treating various bacterial infections.
Sulfonamides , Co-trimoxazole , urinary anti septicJeenaJoy10
This document discusses sulfonamides, cotrimoxazole, and urinary antiseptics. It provides information on the classification, mechanism of action, pharmacokinetics, uses, and adverse effects of sulfonamides. It also summarizes the rationale for combining trimethoprim and sulfamethoxazole in cotrimoxazole, its mechanism of action and uses. Finally, it classifies drugs used for urinary tract infections and provides details on nitrofurantoin, nalidixic acid, and methenamine mandelate which are commonly used urinary antiseptics.
This document discusses Polypodium leucotomos, an herbal extract from the fern plant. It provides details on the botanical validation, chemical composition analysis, biological validation, and technological development of Fernblock, a specific P. leucotomos extract. The extract has been shown to have antioxidant and anti-inflammatory properties. It inhibits UV-induced free radical generation, apoptosis, and immunosuppression. Studies demonstrate it can protect against UV damage, reduce photoinflammation, and help prevent photodamage and photoaging from long-term sun exposure. P. leucotomos is a promising natural photoprotective agent that provides benefits beyond traditional sunscreens.
The document summarizes pesticide metabolism in three phases. Phase 1 involves oxidation, reduction, and hydrolysis reactions mediated primarily by cytochrome P450 enzymes. Phase 2 involves conjugating pesticide metabolites to sugars, amino acids, and glutathione, increasing water solubility. Phase 3 further processes some phase 2 conjugates. The document also discusses pesticide bioremediation using microorganisms and enzymes, as well as the role of plant rhizospheres and chemical safeners in degradation.
The document discusses the mode of action and mechanism of action of herbicides. It defines mode of action as the sequence of events from initial contact of the herbicide with the plant to its ultimate effect, including anatomical, physiological and biochemical responses. Mechanism of action refers specifically to the biochemical and physiological reactions that cause the ultimate herbicidal effect. It provides examples of herbicide absorption, translocation, metabolism, and target sites in plants, as well as discussing the mode of action of several common herbicide classes like phenoxy acids, triazines, sulfonylureas, and glyphosate.
The Mode of Action of herbicides is important for understanding the management , classification and hierarchy of the herbicides. It also provides an insight into herbicide resistance , which continues to be a problem in sustainable agricultural management .
This document discusses the metabolism of xenobiotics, or foreign chemicals, in the body. It notes that xenobiotics are mostly lipophilic and cannot be easily cleared from the body. Their metabolism involves two phases - in the first phase enzymes like cytochrome P450 modify xenobiotics through reactions like hydroxylation and oxidation, while the second phase involves conjugating the substances to make them more water soluble and able to be excreted, through processes like glucuronidation and sulfation. Factors like genetic variability and drug interactions can impact an individual's ability to metabolize different xenobiotics. The document provides many examples of common xenobiotics and discusses how their metabolism can sometimes produce toxic effects.
Real-time driver monitoring is one of the easiest ways to make fleet management efficient as well as seamless. Connected vehicle solutions such as fleet GPS trackers and associated software help businesses in several ways. Refer to the post below for more details.
This document summarizes a seminar presentation on antineoplastic agents. It defines antineoplastic agents as those used to prevent abnormal or uncontrolled cell growth, also known as anticancer agents. The document classifies antineoplastic agents into seven categories - alkylating agents, antimetabolites, plant products, antibiotics, hormones, immunotherapy agents, and miscellaneous agents. For each category, examples are provided and brief descriptions of mechanisms of action and uses. Syntheses of cyclophosphamide and chlorambucil are also outlined.
This document provides a classification and overview of various anti-neoplastic or anticancer drugs. It discusses four main classes: 1) alkylating agents such as cisplatin and cyclophosphamide, 2) antimetabolites including methotrexate and fluorouracil, 3) natural products including vincristine and paclitaxel, and 4) hormones and antagonists like tamoxifen. It then provides more detailed information about the mechanisms and structure-activity relationships of selected drugs, including methotrexate, mercapturine, and tamoxifen.
Plant responses to oxidative stress can cause physiological damage at the lipid, protein, and DNA levels. Physiologically, lipid peroxidation disrupts cell membranes, protein oxidation alters structure and function, and DNA oxidation causes mutations. Biochemically, plants have developed defense mechanisms including superoxide dismutase, catalase, peroxidase, and glutathione to neutralize reactive oxygen species. Glutathione functions in redox reactions and membrane stabilization. Plants also produce antioxidants like carotenoids to counteract oxidative stress and protect cellular components from free radical damage.
Secondary metabolites and abiotic stress-1.pptx66AreejFatima
Secondary metabolites are compounds produced by plants that are not essential for basic plant functions but help plants adapt to environmental stresses. They include phenolic compounds, alkaloids, and terpenes. The document discusses how abiotic stresses like drought, salinity, and temperature affect plant physiology and metabolism. It provides examples of how the secondary metabolite glutathione can help mitigate the effects of salt stress in pea plants by improving factors like chlorophyll content, photosynthesis, and proline levels. The role of secondary metabolites in helping plants tolerate abiotic stress conditions is explored.
Antimetabolites are structurally similar to normal cell compounds and interfere with purine or pyrimidine synthesis or incorporation into DNA/RNA. Common antimetabolites include methotrexate, 6-mercaptopurine, fludarabine, cladribine, 5-fluorouracil, capecitabine, cytarabine, and azacitidine. They are cell cycle specific and used to treat cancers like leukemia, lymphoma, lung cancer, and breast cancer. Common side effects include nausea, vomiting, diarrhea, myelosuppression, and renal toxicity.
Chemical conversion of a substance mediated by living organisms or enzymes
Can result in DETOXIFICATION and BIOACTIVATION
Vital to survive
Key in defense mechanism
In this section, we describe folate antagonists and most of the slides are cited from:
1- Lippincott's Illustrated Pharmacology
2- KD Triphati Pharmacology
3- Basic Katzung Pharmacology
Malaria vaccines cum antimalaria drugs, by bdollarbernard bahaah
This presentation slides give an upto date information on antimalaria drugs and vaccines. It can be used for academic purpose or some other purpose. It highlights some of the successes and potentials of antimalaria drugs.
This document was prepared by Afifa Binta Saifuddin and her group members for the assignment purpose for Department of Pharmacy, East West University, Bangladesh. Uploaded by Tousif Azmain.
The impurities in pharmaceuticals are unwanted chemicals that remain with the active pharmaceutical ingredients
(APIs) or develop during formulation or upon aging of both API and formulation.
This document outlines lectures from a pharmacology course on antibiotics that inhibit cell wall synthesis, protein synthesis, and nucleic acid synthesis. The lectures cover penicillins, cephalosporins, aminoglycosides, sulfonamides, trimethoprim, tetracyclines, macrolides, and chloramphenicol. For each class of antibiotics, the lectures aim to describe their mechanism of action, pharmacokinetics, clinical uses, and adverse effects. The goal is for students to understand how different classes of antibiotics work and their proper use in treating various bacterial infections.
Sulfonamides , Co-trimoxazole , urinary anti septicJeenaJoy10
This document discusses sulfonamides, cotrimoxazole, and urinary antiseptics. It provides information on the classification, mechanism of action, pharmacokinetics, uses, and adverse effects of sulfonamides. It also summarizes the rationale for combining trimethoprim and sulfamethoxazole in cotrimoxazole, its mechanism of action and uses. Finally, it classifies drugs used for urinary tract infections and provides details on nitrofurantoin, nalidixic acid, and methenamine mandelate which are commonly used urinary antiseptics.
This document discusses Polypodium leucotomos, an herbal extract from the fern plant. It provides details on the botanical validation, chemical composition analysis, biological validation, and technological development of Fernblock, a specific P. leucotomos extract. The extract has been shown to have antioxidant and anti-inflammatory properties. It inhibits UV-induced free radical generation, apoptosis, and immunosuppression. Studies demonstrate it can protect against UV damage, reduce photoinflammation, and help prevent photodamage and photoaging from long-term sun exposure. P. leucotomos is a promising natural photoprotective agent that provides benefits beyond traditional sunscreens.
The document summarizes pesticide metabolism in three phases. Phase 1 involves oxidation, reduction, and hydrolysis reactions mediated primarily by cytochrome P450 enzymes. Phase 2 involves conjugating pesticide metabolites to sugars, amino acids, and glutathione, increasing water solubility. Phase 3 further processes some phase 2 conjugates. The document also discusses pesticide bioremediation using microorganisms and enzymes, as well as the role of plant rhizospheres and chemical safeners in degradation.
The document discusses the mode of action and mechanism of action of herbicides. It defines mode of action as the sequence of events from initial contact of the herbicide with the plant to its ultimate effect, including anatomical, physiological and biochemical responses. Mechanism of action refers specifically to the biochemical and physiological reactions that cause the ultimate herbicidal effect. It provides examples of herbicide absorption, translocation, metabolism, and target sites in plants, as well as discussing the mode of action of several common herbicide classes like phenoxy acids, triazines, sulfonylureas, and glyphosate.
The Mode of Action of herbicides is important for understanding the management , classification and hierarchy of the herbicides. It also provides an insight into herbicide resistance , which continues to be a problem in sustainable agricultural management .
This document discusses the metabolism of xenobiotics, or foreign chemicals, in the body. It notes that xenobiotics are mostly lipophilic and cannot be easily cleared from the body. Their metabolism involves two phases - in the first phase enzymes like cytochrome P450 modify xenobiotics through reactions like hydroxylation and oxidation, while the second phase involves conjugating the substances to make them more water soluble and able to be excreted, through processes like glucuronidation and sulfation. Factors like genetic variability and drug interactions can impact an individual's ability to metabolize different xenobiotics. The document provides many examples of common xenobiotics and discusses how their metabolism can sometimes produce toxic effects.
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Sulfonamides
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2. PPH 308: MEDICINAL CHEMISTRY - II Unit: II: Sulfonamides
Lecturer Notes_Dr. S. Mondal_B. Pharm 6th
Semester_GITAM (Deemed to be University) Page | 1
E-mail: logonchemistry@gmail.com
Sulfonamides: Classification, mode of action, uses and structure activity relationship of the following
classes of drugs; Synthesis of Sulphadiazine, Sulphamethoxazole, Sulphacetamide sodium
- Sulfonamide drugs were the first antimicrobial drugs. The first sulfonamide was trade named Prontosil, which is a
prodrug Prontosil, the first commercially available antibacterial with a relatively broad effect (against Gram-
positive cocci but not against enterobacteria).
Prontosil The structure of the sulfonamide group
Mechanism of action of Sulfonamide:
- PABA is an essential nutrient for some bacteria and is sometimes called Vitamin Bx However, PABA is not
essential to human health, and is therefore not officially classified as a vitamin. Although humans lack the ability to
synthesize folate from PABA, it is sometimes marketed as an essential nutrient under the promise that it can
stimulate intestinal bacteria.
- PABA is an intermediate in bacterial synthesis of folate. Sulfonamides are chemically similar to PABA, and their
antibacterial activity is due to their ability to interfere with conversion of PABA to folate by dihydropteroate
synthetase, and subsequent utilization, by bacteria.
- Dihydropteroate synthetase is an enzyme.It produces dihydropteroate in bacteria, but does not function in humans.
This makes it a useful target for sulfonamide antibiotics, which compete with the PABA precursor.
- It acts upon 4-Aminobenzoic acid (PABA} and dihydropteridine-hydroxymethyl-pyrophosphate.
- In bacteria, antibacterial sulfonamides act as competitive inhibitors of the enzyme dihydropteroate synthetase,
DHPS. DHPS catalyses the conversion of PABA (para-aminobenzoate) to dihydropteroate, a key step in folate
synthesis. Folate is necessary for the cell to synthesize nucleic acids (nucleic acids are essential building blocks of
DNA and RNA), and in its absence cells will be unable to divide. Hence the sulfonamide antibacterials exhibit a
bacteriostatic rather than bactericidal effect.
- Folate is not synthesized in mammalian cells, but is instead a dietary requirement. This explains the selective
toxicity to bacterial cells of these drugs. These antibiotics are used to treat pneumocystis jiroveci pneumonia,
urinary tract infections, shigellosis, and certain protozoan infections. The sulfonamide chemical moiety is also
present in other medications that are not antimicrobials, including thiazide diuretics (including hydrochorothiazide,
metolazone, and indapamide, among others), sulfonylureas (including glipizide, glyburide, among others), and
acetazolamide.
3. PPH 308: MEDICINAL CHEMISTRY - II Unit: II: Sulfonamides
Lecturer Notes_Dr. S. Mondal_B. Pharm 6th
Semester_GITAM (Deemed to be University) Page | 2
E-mail: logonchemistry@gmail.com
- Both trimethoprim and the sulfonamides interfere with folate metabolism in the bacterial cell by competitively
blocking the biosynthesis of tetrahydrofolate, which acts as a carrier of one-carbon fragments and is necessary for
the ultimate synthesis of DNA, RNA and bacterial cell wall proteins
4-Aminobenzoic acid
(PABA)
Tetrahydrofolic acid Folic acid
4. PPH 308: MEDICINAL CHEMISTRY - II Unit: II: Sulfonamides
Lecturer Notes_Dr. S. Mondal_B. Pharm 6th
Semester_GITAM (Deemed to be University) Page | 3
E-mail: logonchemistry@gmail.com
Why sulfanilide or sulfonamide inhibit folic acid synthesis mechanism
- Cells use folic acid as a single-carbon atom building block for the construction of nucleic acids and other biological
molecules. Inhibition of this process prevents growth and reproduction, but does not directly lead to cell death.
Bacteria synthesize folic acid from 2-amino-4-oxo-6-methylpteridine diphosphate, p-aminobenzoic acid (PABA),
and L-glutamic acid. Because sulfa drugs are structural mimics of PABA they may bind to dihydropteroate
synthetase, one of the enzymes necessary for folic acid synthesis (reversible and competitive inhibition). With this
enzyme inhibited, folic acid synthesis is prevented and cell growth and reproduction are halted.
- In addition, the two molecules are of nearly identical length (6.7 Å for PABA versus 6.9 Å for sulfanilide), both are
roughly flat, and both have an equal distribution of charge (δ+
on the NH2 group and δ-
on the COOH or SO2NHR
groups). This effect can be seen more clearly by examining the electrostatic potential surfaces of these molecules.
Why bacterial dihydrofolate reductase is many times more sensitive to Trimethoprim
than is equivalent enzyme in humans?
- In microorganism human one of the key enzyme dihydrofolate reductase which reduces dihydrofolate to
tetrahydrofolate is many more sensitive to folate antagonist trimethoprim in bacteria than in human because of IC50
values (the concentration causing 50% inhibition).
Inhibitor
IC50 (micro mol/lit) for dihydrofolate reductase enzyme
Human Protozal Bacteria
Trimethoprim 260 0.07 0.005
Pyrimethamine 0.7 0.0005 2.5
Methotrexate 0.001 0.1 Inactive
5. PPH 308: MEDICINAL CHEMISTRY - II Unit: II: Sulfonamides
Lecturer Notes_Dr. S. Mondal_B. Pharm 6th
Semester_GITAM (Deemed to be University) Page | 4
E-mail: logonchemistry@gmail.com
Side effects:
- Sulfonamides have the potential to cause a variety of untoward reactions, including urinary tract disorders,
haemopoietic disorders, and hypersensitivity reactions.
- When used in large dose, it may develop a strong allergic reaction. One of the most serious is Stevens Johnson
syndrome(or toxic epidermal necrolysis).
- Some of the original sulfonamide drugs were derived from azo dyes and had the interesting effect of
temporarily turning the patient red.
- N.B- Stevens-Johnson syndrome (SJS) is a life-threatening condition affecting the skin, in which due to cell
death the epidermis separates from the dermis. The syndrome is thought to be a hypersensitivity complex
affecting the skin and the mucous membranes.
Adverse reactions:
i) The most common manifestation of a hypersensitivity reaction to sulfa drugs are rash and hives.
However, there are several life-threatening manifestations of hypersensitivity to sulfa drugs, including
Stevens-Johnson syndrome, toxic epidermal necrolysis, agranulocytosis, hemolytic anemia,
thrombocytopenia, and fulminant hepatic necrosis, among others
ii) The sulfonamide antibiotic chemical structures are implicated in the hypersensitivity reactions associated
with the class.
- The first is the N1
heterocyclic ring, which causes a type I hypersensitivity reaction.
- The second is the N4
amino nitrogen that, in a stereospecific process, forms reactive metabolites that cause
either direct cytotoxicity or immunologic response.
Note By:
Folic acid: Folic acid and folate (the anion form) are forms of the water-soluble Vitamin B9. These occur naturally in
food and can also be taken as supplements. Folate gets its name from the Latin word folium.
Biological roles of folate-
i) Folate is necessary for the production and maintenance of new cells. This is especially important during periods of
rapid cell division and growth such as infancy and pregnancy. Folate is needed to synthesize DNA bases (most
notably thymine, but also purine bases) needed for DNA replication. Thus folate deficiency hinders DNA
synthesis and cell division, affecting most notably bone marrow and cancer, both of which participate in rapid cell
division.
ii) In the form of a series of tetrahydrofolate (THF) compounds, folate derivatives are substrates in a number of
single- carbon-transfer reactions, and also are involved in the synthesis of dTMP (2′-deoxythymidine-5′-
phosphate) from dUMP (2′-deoxyuridine-5′-phosphate). It is a substrate for an important reaction that involves
vitamin B12 and it is necessary for the synthesis of DNA, required for all dividing cells.
The pathway leading to the formation of tetrahydrofolate (FH4) begins when folate (F) is reduced to dihydrofolate
(DHF) (FH2), which is then reduced to THF. Dihydrofolate reductase catalyses the last step.Vitamin B3 in the form of
NADPH is a necessary cofactor for both steps of the synthesis
6. PPH 308: MEDICINAL CHEMISTRY - II Unit: II: Sulfonamides
Lecturer Notes_Dr. S. Mondal_B. Pharm 6th
Semester_GITAM (Deemed to be University) Page | 5
E-mail: logonchemistry@gmail.com
SAR of Sulphonamides
The major features of SAR of sulphonamides include the following:
- Sulphanilamide skeleton is the minimum structural requirement for antibacterial activity.
- The amino- and sulphonyl-groups on the benzene ring are essential and should be in 1 and 4 position.
- The N-4 amino group could be modified to be prodrugs, which are converted to free amino function in vivo.
- Sulphur atom should be directly linked to the benzene ring.
- Replacement of benzene ring by other ring systems or the introduction of additional substituents on it decreases or
abolishes its activity.
- Exchange of the –SO2NH group by –CONH reduces the activity.
- On N-1-substituted sulphonamides, activity varies with the nature of the substituent at the amino group. With
substituents imparting electron-rich characters to SO2 group, bacteriostatic activity increases.
- Heterocyclic substituents lead to highly potent derivatives, while sulphonamides, which contain a single benzene
ring at N-1 position, are considerably more toxic than heterocyclic ring analogues.
- The free aromatic amino groups should reside para to the sulphonamide group. Its replacement at ortho or meta
position results in compounds devoid of antibacterial activity.
- The active form of sulphonamide is the ionized, maximum activity that is observed between the pKa values 6.6–
7.4.
- Substitutions in the benzene ring of sulphonamides produced inactive compounds.
- Substitution of free sulphonic acid (–SO3H) group for sulphonamido function destroys the activity, but
replacement by a sulphinic acid group (–SO2H) and acetylation of N-4 position retains back the activity.
- Meta-Sulphonamides bind to the basic centres of arginine, histidine, and lysine sites of proteins. The binding
groups are alkyl, alkoxy, and halides. The binding affects the activity of sulphonamides; protein binding appears to
modulate the availability of the drug and its half-life.
- The lipid solubility influences the pharmacokinetic and antibacterial activity, and so increases the half-life and
antibacterial activity in vitro.
7. PPH 308: MEDICINAL CHEMISTRY - II Unit: II: Sulfonamides
Lecturer Notes_Dr. S. Mondal_B. Pharm 6th
Semester_GITAM (Deemed to be University) Page | 6
E-mail: logonchemistry@gmail.com
Sulphonamides can be classified in various ways:
1. On the basis of the site of action
(i) Sulphonamides for general infection: Sulphanilamide, Sulphapyridine, Sulphadiazine, Sulphamethoxacine,
Sulphamethoxazole.
(ii) Sulphonamides for urinary tract infections: Sulphaisoxazole, Sulphathiazole.
(iii) Sulphonamides for intestinal infections: Phthalylsulphathiazole, Succinyl sulphathiazole, Sulphasalazine.
(iv) Sulphonamides for local infections: Sulpahacetamide, Mafenamide, Silver sulphadiazine.
(v) Sulphonamides for dermatitis: Dapsone, Solapsone.
(vi) Sulphonamides in combination: Trimethoprim with Sulphamethoxazole.
2. On the basis of the pharmacokinetic properties
(i) Poorly absorbed sulphonamides (locally acting sulphonamides): Sulphasalazine, Phthalylsulphathiazole,
Sulphaguanidine, Salicylazo sulphapyridine, Succinyl sulpha thiazole.
(ii) Rapidly absorbed and rapidly excreted (systemic sulphanamides): Sulphamethoxazole, Sulphaisoxazole,
Sulphadiazine, Sulphadimidine, Sulphafurazole, Sulphasomidine, Sulphamethiazole, Sulphacetamide
Sulphachlorpyridazine.
(iii) Topically used sulphonamides: Sulphacetamide, Mafenide, Sulphathiazole, Silver sulphadiazine.
3. On the basis of the pharmacological activity
(i) Antibacterial agents: Sulphadiazine, Sulfi soxazole.
(ii) Drugs used in dermatitis: Dapsone.
4. On the basis of the duration of action
(i) Extra-long-acting sulphonamides (half-life greater than 50 h): Sulphasalazine, Sulphaclomide, Sulphalene.
(ii) Long-acting sulphonamides (half-life greater than 24 h): Sulphadoxine, Sulphadimethoxine, Sulphamethoxy
pyridazine, Sulphamethoxydiazine, Sulphaphenazole, Sulphamethoxine.
(iii) Intermediate-acting sulphonamides (half-life between 10–24 h): Sulphasomizole, Sulphamethoxazole.
(iv) Short-acting sulphonamides (half-life less than 20 h): Sulphamethiazole, sulphaisoxazole.
(v) Injectable (soluble sulpha drugs): Sulphafurazole, Sulphadiazine, Sulphamethoxine.
5. On the basis of the chemical structure
(i) N-1 substituted sulphonamide: Sulphadiazine, Sulphacetamide, Sulphadimidine.
(ii) N-4 substituted sulphonamides (prodrugs): Prontosil.
(iii) Both N-1 and N-4 substituted sulphonamides: Succinyl sulphathiazole, Phthalylsulphathiazole.
(iv) Miscellaneous: Mefenide sodium.
8. PPH 308: MEDICINAL CHEMISTRY - II Unit: II: Sulfonamides
Lecturer Notes_Dr. S. Mondal_B. Pharm 6th
Semester_GITAM (Deemed to be University) Page | 7
E-mail: logonchemistry@gmail.com
Structures of Sulfonamide derivatives:
9. PPH 308: MEDICINAL CHEMISTRY - II Unit: II: Sulfonamides
Lecturer Notes_Dr. S. Mondal_B. Pharm 6th
Semester_GITAM (Deemed to be University) Page | 8
E-mail: logonchemistry@gmail.com
Synthesis of Sulphanilamide
10. PPH 308: MEDICINAL CHEMISTRY - II Unit: II: Sulfonamides
Lecturer Notes_Dr. S. Mondal_B. Pharm 6th
Semester_GITAM (Deemed to be University) Page | 9
E-mail: logonchemistry@gmail.com
Synthesis of Sulphacetamide
Synthesis of Sulphamethoxazole
11. PPH 308: MEDICINAL CHEMISTRY - II Unit: II: Sulfonamides
Lecturer Notes_Dr. S. Mondal_B. Pharm 6th
Semester_GITAM (Deemed to be University) Page | 10
E-mail: logonchemistry@gmail.com
Synthesis of Sulphadiazine
12. PPH 308: MEDICINAL CHEMISTRY - II Unit: II: Sulfonamides
Lecturer Notes_Dr. S. Mondal_B. Pharm 6th
Semester_GITAM (Deemed to be University) Page | 11
E-mail: logonchemistry@gmail.com
Trimethoprim/Sulphamethoxazole
- Trimethoprim/Sulphamethoxazole (TMP/SMX), also known as co-trimoxazole.
- It is an antibiotic used to treat a variety of bacterial infections.
- It consists of one part trimethoprim to five parts sulfamethoxazole.
- It is used for urinary tract infections, skin infections, travelers' diarrhea, respiratory tract infections, and cholera,
among others. It may be used both to treat and prevent pneumocystis pneumonia in people with HIV/AIDS.
- It can be given by orally or intravenously.
- Common side effects include nausea, vomiting, rash, and diarrhea.
- Severe allergic reactions and Clostridium difficile diarrhea may occasionally occur.
- Its use near the end of pregnancy is not recommended.
- It appears to be safe for use during breastfeeding as long as the baby is healthy.
- TMP/SMX generally results in bacterial death. It works by blocking the making of folate by the bacteria
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