Structure activity relationship studies of 1,4-benzodiazepines have been discussed especially
with their effects as antianxiety and anticonvulsants. The currently available benzodiazepines are
associated with various side effects. Nowadays the purpose of these studies is to minimize side effects
with these drugs. A very little alteration is possible on the benzene ring while the modification can be
done on the diazepine ring. It can adopt the different conformations and in some cases some aromatic
and heterocyclic rings have been fused with this part in order to see the effect of these conformation
blockers on the pharmacological activity. The structure activity studies are also linked to molecular
modeling studies. This is important in adding some information for the interaction of these drugs with
the receptors and how this interaction can be improved.
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
stereochemistry and drug action ; basic introduction about stereochemistry and stereoisomers ; pharmacokinetic and pharmacodynamics concept of stereochemistry ; easson Stedman hypothesis ; stereo selectivity criteria .
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
stereochemistry and drug action ; basic introduction about stereochemistry and stereoisomers ; pharmacokinetic and pharmacodynamics concept of stereochemistry ; easson Stedman hypothesis ; stereo selectivity criteria .
For B Pharmacy and M Pharmacy Students
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Spectrophotometric Determination of Drugs Using Iodine As Analytical ReagentIOSR Journals
Six drugs viz., Astemizole, Cisapride, Domperidone, Pantoprazole, Rabeprazole and Trazadone were tested for the formation of charge transfer complexes with Iodine. Each of these drugs turned the violet coloured i.e iodine , in CH2Cl2, to brown and exhibited a new band at 366nm in addition to the original band of iodine at 510nm due to anion of the reagent whose intensity increased with increase in the concentration of the drugs and formed a basis for quantitative determination of the drugs. The complexes were found to have 1:1 composition and have stability of the order 10 3 to 10 4. The effect of the concentration reagent, polarity of solvent, interference of excipients have been studied and optimized. Dichloroethane (DCE) was found to be suitable solvent for the analysis. The methods have been validated in terms of ICH guidelines and applied to the quantification of pharmaceuticals. The variation of slopes of calibration plots and stability constants of the complexes are discussed in terms of structures of the drugs.
Physical and Structural Characterization of Biofield Treated Imidazole Deriva...albertdivis
The Aim of present study was to evaluate the impact of biofield treatment on two imidazole derivatives (i.e., imidazole and 2-methylimidazole) by various analytical methods.
Synthesis and Characterization of Some Pyrazole Based Heterocyclic Compoundsijtsrd
The reaction of phenyl hydrazine with ethyl acetoacetate gave 3 methyl 1 phenyl 5 pyrazolone 1 , which then treated with malonitrile and benzaldehyde to give 6 amino 3 methyl 1,4 dihydropyrano 2,3 b pyrazole 5 carbonitrile 2 which considered assynthone for prepare some new pyrazole derivatives 3a j .The structure of the prepared compounds was suggested in the IR , 1 H NMR, 13 C NMR and UV Spectroscopy. Many steps starting from esterification of isophthalic acid to yield diester compound I which was converted to their acid hydrazide II , then the later compound reacted with ethylacetoacetate to yield pyrazol 5 one compound III . Afterword added acetyl chloride to give the compound IV , there action of this compound with theiosemicarbazide ledto produce a new carbothioamide compound V , Which was reacted with ethyl chloro acetate to yield thethioxoimidazolidin compound VI . The condensation reaction of this compound with different substituted aldehyde give new alkene derivatives VII a d. The synthesized compounds were characterized by melting points , FT IR ,1H NMR and Mass spectroscopy. Munesh Sharma "Synthesis and Characterization of Some Pyrazole Based Heterocyclic Compounds" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-6 | Issue-5 , August 2022, URL: https://www.ijtsrd.com/papers/ijtsrd51723.pdf Paper URL: https://www.ijtsrd.com/chemistry/other/51723/synthesis-and-characterization-of-some-pyrazole-based-heterocyclic-compounds/munesh-sharma
Recent Advancement and Patents of the Lipid Polymer Hybrid Nanoparticlespeertechzpublication
In recent years, robustness and surface engineering of dosage form made improvement in
pharmacokinetics with decrease in dose of drug. Specifi city with adherence of ligands has now become
the reality as surface modifi cation can easily deceive phagocytic system. Lipid molecules ensures the
release of drug at lymphatic system, entrapment of polymeric nanoparticles in lipoidal core led to the
avoidance of disadvantage of low entrapment effi ciency if use of hydrophobic drug with hydrophobic
polymer becomes essential. Various studies have been published and the best formulations with optimal
In vitro and In vivo results are highlighted in this paper. In this review most advanced researches and
accepted patents were discussed so to act as a medium for getting everything regarding lipid polymer
hybrid particles under one umbrella.
Vibrational Characterization and Antioxidant Activity of Newly Synthesized Ga...peertechzpublication
The gallium(III) complex of orotic acid (HOA) was synthesized and its structure was determined
by means of analytical and spectral analyses. Detailed vibrational analysis of HOA, sodium salt of HOA
(NaOA) and Ga(III)-OA systems based on both the calculated and experimental spectra confi rmed the
suggested metal-ligand binding mode. Signifi cant differences in the IR and Raman spectra of the complex
were observed as compared to the spectra of the ligand and confi rmed the suggested metal-ligand
binding mode.
Synthesis and Antimicrobial Evaluation of Some Nitro-Mannich Bases Derived fr...peertechzpublication
The present work focused on exploring the reactivity of β-nitrostyrene towards Mannich reaction
with different approaches. The synthesized nitro-Mannich bases were tested as antimicrobial agents
that showed high activity against both gram positive and gram negative bacteria.
Microwave Irradated Synthesis, Characterization and Evaluation for their Antibacterial and Larvicidal Activities of some Novel Chalcone and Isoxazole Substituted 9-Anilino Acridines
drug delivery and formulation sciences in the most intelligent
way. This should be attained to fulfi l the ultimate goal for all
scientists to leave their experimental results all over the years
as footsteps for followers to walk on.
Mycobacterium Tuberculosis cause severe disease of lungs known as Tuberculosis. It is a major cause
of morbidity and mortality even in the emerging countries also. However, to prepare an antibiotics drug against Mycobacterium tuberculosis is a major challenge
Mini tablets are solid dosage forms with a diameter ≤ 3 mm and separated into subunits of conventional
tablets. Production methods are similar to standard tablets, but the only difference is the use of multiple
punches. They have advantageous for use in patients suffering from swallowing difficulty and receiving multiple drug treatment.
Drug-Drug interactions (DDI) is a serious clinical issue. An important mechanism underlying of DDI, is
induction or inhibition of drug metabolizing enzymes (DMEs) and transporters that mediate metabolism, cellular uptake and efflux of xenobiotics. DDI cannot be avoided in many cases, as they belong to routine medical practice.
In recent years, robustness and surface engineering of dosage form made improvement in pharmacokinetics with decrease in dose of drug. Specificity with adherence of ligands has now become the reality as surface modifi cation can easily deceive phagocytic system. Lipid molecules ensures the
release of drug at lymphatic system, entrapment of polymeric nanoparticles in lipoidal core led to the
avoidance of disadvantage of low entrapment effi ciency if use of hydrophobic drug with hydrophobic polymer becomes essential. Various studies have been published and the best formulations with optimal In vitro and In vivo results are highlighted in this paper. In this review most advanced researches and accepted patents were discussed so to act as a medium for getting everything regarding lipid polymer hybrid particles under one umbrella.
Few species are standardized and have been used as test organisms around the world in
ecotoxicological assays. In the case of sediment assessment, there are only two amphipod species
(Tiburonella viscana and Grandidierella bonnieroides) standardized protocols for toxicity test in South
Atlantic region
Gigantic submarine landslides are among the most energetic events on the Earth surface. During the
Late Pleistocene the Mediterranean Sea was the scenario of a 9 number of such events, some of whose
geological fi ngerprints are the 500 km3 mass transport deposit SL2 at the Nile delta fan (dated at ca. 110
ka BP) and the Herodotus Basing Megaturbidite (HBM, a 400 km3 deposit dated at ca. 27.1 ka BP).
Natural frequency of structure mainly depends on mass and stiffness. Stiffness is bound to change
after structural damage. Hence, natural frequency starts to decline.
In this study, the green-lipped mussels Perna viridis were collected from a high activity sampling at
Senibong in the Straits of Johore and two relatively clean sites with fi sh aquacultural activity at Bagan
Tiang (Perak) and Sg. Semerak (Kelantan). The mussels were dissected by gender into byssus, crystalline
style, foot, gill, gonad, mantle and muscle.
The current study examines the generation and propagation of a Third order solitary water wave along
the channel. Surface displacement and wave profi le prediction challenges are interesting subjects in the
fi eld of marine engineering and many researchers have tried to investigate these parameters. To study the
wave propagation problem, here, fi rstly the meshless Incompressible Smoothed Particle Hydrodynamics
(ISPH) numerical method is described. Secondly,
The growth of data and its effi cient handling is becoming more popular trend in recent years bringing
new challenges to explore new avenues. Data analytics can be done more effi ciently with the availability of
distributed architecture of “Not Only SQL” NoSQL databases.
In modern mechanical engineering and steelwork the use of cold-rolled steel sections is a
standard method. These sections should be mechanically stable on the one hand and cost efficient on
the other hand. To decide what profile suits for a certain case is a constrained optimization problem which is in general non convex, i.e. several local optima exist.
Few species are standardized and have been used as test organisms around the world in
ecotoxicological assays. In the case of sediment assessment, there are only two amphipod species
(Tiburonella viscana and Grandidierella bonnieroides) standardized protocols for toxicity test in South
Atlantic region.
Gigantic submarine landslides are among the most energetic events on the Earth surface. During the
Late Pleistocene the Mediterranean Sea was the scenario of a 9 number of such events, some of whose
geological fi ngerprints are the 500 km3 mass transport deposit SL2 at the Nile delta fan (dated at ca. 110
ka BP) and the Herodotus Basing Megaturbidite (HBM, a 400 km3 deposit dated at ca. 27.1 ka BP). This
paper presents an exploratory study on the tsunamigenic potential of these slides by using a numerical
model based on the 2D depth-averaged non-linear barotropic shallow water equations.
Introduction: The aim of this study is to evaluate, within the scope of an experimental design, to
what extent the assessment of two different settings of prepared cavities, based on video sequences,
containing digital analysis tools of the prepCheck software, as well as to what extent they deviate from one another and are reliable. Materials and Methods: For
Predicting the amount of electricity produced in a power plant is very important for today’s economy.
Oven Power (MW), Boiler Input Gas Temperature, Superheated Steam Amount, ID-Fan Speed, Feeding
Water Tank data affect the electricity production.
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
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NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
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Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
Evaluation of antidepressant activity of clitoris ternatea in animals
Recent Structure Activity Relationship Studies of 1,4-Benzodiazepines
1. Open Journal of Chemistry eertechz
Citation: Mohsin NA, Qadir MI (2015) Recent Structure Activity Relationship Studies of 1,4-Benzodiazepines. Open J Chem 1(1): 008-0012.
008
Abstract
Structure activity relationship studies of 1,4-benzodiazepines have been discussed especially
with their effects as antianxiety and anticonvulsants. The currently available benzodiazepines are
associated with various side effects. Nowadays the purpose of these studies is to minimize side effects
with these drugs. A very little alteration is possible on the benzene ring while the modification can be
done on the diazepine ring. It can adopt the different conformations and in some cases some aromatic
and heterocyclic rings have been fused with this part in order to see the effect of these conformation
blockers on the pharmacological activity. The structure activity studies are also linked to molecular
modeling studies. This is important in adding some information for the interaction of these drugs with
the receptors and how this interaction can be improved.
Chemistry and biological activity
The discovery of BDZs dates back to 1950 and the first agent
which was introduced in the market was chlordiazepoxide.
Diazepam, the second member of this series was more active [7].
Introduction of substituent is very important in BDZs especially the
position 7. The potency of these compounds also increases by adding
the substituent’s in ring B and C [8]. Triazolo BDZs which contains
triazole ring fused with diazepine nucleus are most potent agents in
this class [9,10](Figure 1).
Furan and thiophene are the bioisosteres of the phenyl ring
[11]. 5-thienyl and 5-furyl substituted BDZs were synthesized and
evaluated for their affinity at the BDZs receptors in order to get
information about the binding of lipophilic pocket and its effect on
the biological activity. The 5-(2’-thienyl) BDZs showed high affinity
for the BDZs receptors which displaced flunitrazepam from rat
cortical membrane with high affinity and were anticonvulsant and
muscle relaxant. When a bromine atom was substituted at position
4’, the compound was less active. The 5-(3’-thienyl) and 5-(2’-furyl)
were less potent. The 2’-halo substituted phenyl was more potent than
the 2’-thienyl and 2’-furfuryl [12] (Figure 2).
Introduction
Benzodiazepines (BDZs) are the bicyclic heterocyclic compounds
in which benzene ring is fused to seven membered diazepine ring
containing two nitrogen. There are different types of BDZs such as
1,2-benzodiazepines, 1,3-benzodiazepines, 1,4-benzodiazepines,
1,5-benzodiazepines, 2,3-benzodiazepines. 1,4-BDZs possess
anxiolytic, anticonvulsant, muscle relaxant properties. They are
widely used as a treatment of anxiety, insomnia, epilepsy, alcohol
with drawl, for anaesthesia and about 500 million peoples have
been treated with BDZs [1]. There are two types of BDZs receptors,
central BDZs receptors and peripheral BDZs receptors. Physiological
functions of peripheral BDZs receptors are different from the central
BDZs receptors [2]. BDZs produce their effect by binding to the
central BDZs receptors which are located at the post and presynaptic
membranes [3]. Their binding to γ aminobutyric acid (GABAA
)
receptors increases the chloride ion conductance by inducing some
conformational changes and causes inhibition of action potential [4].
BDZs enhance the effect of neurotransmitter GABA at their receptors.
Use of BDZs is increased from the last 15 and 20 years and now
they are widely prescribed. Side effects associated with the use of
these drugs such as drowsiness, tolerance, addiction and withdrawal
potential causes problems [5]. The discovery of selective ligands for
the central BDZs receptors, which have the anxiolytic activity without
producing these side effects, is important. Docking of BDZs with the
GABA receptors determine the binding analysis of drug with BDZs
receptors [6]. The main objective of this is the discovery of product
with narrow spectrum of activities.
In this paper some structure modifications studies carried out on
different position of the 1,4-BDZs in the last two decades have been
summarized. Studies were focused especially on their antianxiety,
anticonvulsant and muscular relaxant effects.
Review Article
Recent Structure Activity
Relationship Studies of
1,4-Benzodiazepines
Noor ul Amin Mohsin1
and Muhammad
Imran Qadir2
*
1
College of pharmacy GC university Faisalabad,
Pakistan
2
Institute of Molecular Biology & Biotechnology,
Bahauddin Zakariya University, Multan, Pakistan
Dates: Received: 06 October, 2015; Accepted: 07
November, 2015; Published: 10 November, 2015
*Corresponding author: Muhammad Imran Qadir,
Assistant Professor, Institute of Molecular Biology &
Biotechnology, Bahauddin Zakariya University, Multan,
Pakistan, E-mail:
www.peertechz.com
Keywords: Benzodiazepines; Structure activity
relationships
N
N
O
R
X
Ring A
Ring C
Ring B
Figure 1:
2. Citation: Mohsin NA, Qadir MI (2015) Recent Structure Activity Relationship Studies of 1,4-Benzodiazepines. Open J Chem 1(1): 008-0012.
Mohsin and Qadir (2015)
009
Azirino BDZs are more lipophilic than the BDZs. Some azirino
compounds were active as anticonvulsant but failed to displace
flumazenil. The activity was evaluated as inhibitor of binding of
flumazenil to the cerebral receptors. The less activity may be related
to steric hindrance of the azirine nucleus so that the phenyl group
cannot adopt the proper conformation for binding or may be due
to the less penetration into the central nervous system (CNS) by
crossing blood brain barrier [13] (Figure 3).
11-aryl-5H-imidazo [2,1-c][1,4] benzodiazepines and their
10,11 dihydro derivatives were prepared to investigate the effect of
additional aromatic ring in the BDZs. The most active compound
was with the 11(2’-thienyl) ring as determined for their potency to
displace flumazenil from the binding site in rat brain. When the
diazepine ring is reduced between positions 10-11, the activity of the
compounds decreases because the reduced compound showed less
affinity for the central GABA receptors as determined by radioligand
binding assay [14] (Figure 4).
4-chloro-pyrimido [4,5-b][1,4] benzodiazepines were synthesized
by a new method. The starting compound was the 4,6-dichloro-
5-nitropyrimidines, amines and different carboxylic acids. By this
method the final compound were obtained in a good yield. Although
these compounds were not evaluated for their tranquilizer activity but
they contain a 1,4-BDZs core and they can be interesting candidate
for the antianxiety and anticonvulsant activity [15] (Figure 5).
Triazole ring system of alprazolam was modified by some
aromatic ring such as pyridine, 4- florophenyl, 6-methoxy-2-
naphthyl, 2-bromo-5-methoxy phenyl. Some of these compounds
showed excellent anticonvulsive activity when compared with
diazepam. These compounds also need further evaluation in order to
clear their therapeutic profile [16] (Figure 6).
Fourdifferentseriesof5-aryl-imidazo[2,1-c][1,4]benzodiazepine
were synthesized and evaluated for their central (flumazenil) and
peripheral (PK11195) BDZs receptors (PBR) affinity. All compounds
were found to be inactive at the central BDZs receptors. For the
peripheral receptors compound 1c and 2 b-c were active. 1c, a
member of methylated carboxamide derivatives was highly active
which indicates the methyl group at position 10 increases the activity.
The introduction of chlorine at position 7 significantly increases the
activity as compared to the unsubstituted analogues indicating that
it might interact with the lipophilic core of PBR. In the oxidized
derivatives the activity is associated with the presence of unsaturation
between positions 10-11 [17] (Figure 7).
N
N
X
O
S
H3C
Figure 2: X=H, F, Cl, N3.
N
N
Cl
Cl
Cl
Figure 3:
N
N
N
Ar
N
H
N
N
Ar
10 11
Figure 4: (Ar = phenyl, p-fluoro phenyl, o-fluoro phenyl, p-methoxy phenyl,
thienyl, furyl).
N
N
R3
N
N
Cl
R2
R1
Figure 5: R1=H, R2=CH3, R3=Cl , F, CH3, OH.
N
N
N
NAr
Cl
F
Figure 6:
3. Citation: Mohsin NA, Qadir MI (2015) Recent Structure Activity Relationship Studies of 1,4-Benzodiazepines. Open J Chem 1(1): 008-0012.
Mohsin and Qadir (2015)
010
a b c d e f
R Cl Cl Cl H H H
R1 H H Cl H H Cl
R2 H Cl H H Cl H
Another approach of fusion of heterocyclic ring with the BDZs
nucleus was the synthesis of 1-[(p-substituted)phenyl]-3a-[(o-and
p-substituted)-phenyl]-5-chloro-9-methylthio-10,3a-dihydro-
[1,2,4]-oxadiazolo [2,3-b][1,4] benzodiazepines. These compounds
are prepared by the reaction of 2-methylthio-5-[(o- p-substituted)-
phenyl]-3H-7-chloro-[1,4] benzodiazepine with the benzonitrile
oxide amoyl chloride and the resultant mixture were purified by
the column chromatography. These compounds also showed the
potential for antianxiety, anticonvulsant activity [18] (Figure 8).
Synthesis of ethyl 8-fluoro-6-(4-nitrophenyl) and ethyl 8-fluoro-
6-(3-nitrophenyl)-4H-imidazo [1,5-a][1,4] benzodiazepine-3-
carboxylates was carried out and their ability to inhibit the binding
of flunitrazepam on the bovine and human cerebral BDZs receptors
(CBR) was evaluated. The second compound was more active as
antianxiety when tested in animals and also did not show side effects of
BDZs. The docking result of this compound with the GABA receptor
showed that the nitro group is involved in hydrogen bonding with the
Thr193 of the receptors [19] (Figure 9).
3-arylamine derivatives of 1,4-benzodiazepine-2-one were
prepared by the reaction of 1-methoxycarbonyl methyl-7-bromo-
5-phenyl-1,2-dihydro-3H-1,4-benzoidazepines-2-one with the
substituted anilines. These compounds were prepared on the basis of
quantitative structure activity relationship (QSAR) studies. Affinity
of the compounds for the central and peripheral BDZs receptors
was determined by radio ligand method by the ability of investigated
compounds to displace competitively radioligand central BDZs
receptor antagonist (Flumazenil) and peripheral BDZs receptors
antagonists (Pk 11195) from their binding sites on BDZs receptors.
Ortho substituted nitro aniline was more active than the para and
Meta nitro aniline and nitro group was determinant of biological
activity [20] (Figure 10).
The introduction of substituted aniline (by imine linkage) at the
position 2 of the BDZs showed increased neurotoxicity particularly
when aniline is substituted at the para position with halogens atom,
the most active in this series was compound with fluoro atom. The
biological activity was determined by rota rod animal model and
ethanol potentiation animal model [21] (Figure 11).
N
N
R
R2
N
R1
O
H3C
1a-f
N
N
R
R2
N
R1
2a-f
Figure 7:
N
N
Cl
O
N
S
CH3
R
Figure 8: R= Cl, Br.
N
N
Br
NO2
OC2H5
O
N
N
Br
OC2H5
O
O2N
Figure 9:
N
N
O
Br
O
H3C
O
NH
R
Figure 10: (R= NO2
).
N
H
N
N
Cl
R
Figure 11: R= H, 3-CH3, 4-F, 2-Cl, 3-Cl 4-Cl,4-Br,2-CH3, 4-NO2, 4-(CH3)2N.
4. Citation: Mohsin NA, Qadir MI (2015) Recent Structure Activity Relationship Studies of 1,4-Benzodiazepines. Open J Chem 1(1): 008-0012.
Mohsin and Qadir (2015)
011
The introduction of benzylidene at the position 3 of the
diazepine ring also produced the potent compounds especially when
the benzylidene is substituted at para position with the electron
withdrawing and lipophilic atom such as halogens. The compounds
were evaluated for antianxiety activity via elevated plus maze
apparatus [22] (Figure 12).
The diazonium salts derived aromatic group were attached
at the position 3 and tested for their anticonvulsant activity.
The compounds exhibited good anticonvulsant activity when
aromatic ring was substituted with chloro, floro and nitro groups
as determined by the maximal electro shock model and inhibition
of pentylenetetrazole induced convulsions. This group seems to be
affecting the conformation of diazepine ring which is significant for
binding with the GABA receptors [23] (Figure 13).
The alkoxy were attached at the position 3 and the resulting
compounds were separated into two enantiomers by chiral
chromatography. The activity of S enantiomer was found greater than
R enantiomer for the cerebral benzodiazepine receptors (CBR) and
peripheral benzodiazepine receptors (PBR) of rat. The selectivity of
compounds for the CBR was greater than the PBR [24] (Figure 14).
Sugar based pyrrole moiety was connected to the BDZs and
evaluated for their GABAA
receptor affinity as an inhibitor of binding
of [3
H]Flunitrazepam. Different structure variation studies showed
that N methylation and halogen substituent are important for the
GABAA
receptor binding. Pyrrole ring adopt a rigid conformation
around the BDZs and in some cases increases the binding of these
compounds. D and L fructose based pyrrole BDZs have different
binding capacity. The biological activities of these compounds were
less than the traditional GABA receptors ligand but they added some
information regarding the conformations of BDZs while binding to
the receptors [25] (Figure 15).
3-substituted 6-phenyl-4H-imidazo [1,5-a][1,4]-benzodiazepine
are the compound containing the substituent at position 3 such as
esters, amides and nitriles. The active compound in this series was
having the ester at this position as determined by their activity to
displace Flumazenil from their binding sites. Upon in vivo evaluation
this compound showed prominent effect without the side effects.
Molecular dynamics studies of the complex of BDZs with the
receptors showed that binding is stable and smaller groups were
active at this position while the larger bulkier groups showed less
binding. The additional imidazo ring in these derivatives is involved
in π - π interactions while the phenyl ring increase the hydrophobic
interactions [26] (Figure 16).
Conclusion
Lot of compounds in the series of 1,4-BDZs have been synthesized
with the substituent’s at almost all the positions. The diazepine ring
N
H
N
O
Cl
CH
R
Figure 12: (R= 4-Cl, 2-Cl, 3,4-OCH3, 3-OH, 4-OH, 2-OH, 4-OCH3, 4-F,
4-Br,4-CH3, 4-(CH3)2N ).
N
H
N
O
Cl
N N
R
Figure 13: (R= 2-Cl, 3-Cl, 4-Cl, 2,4-di NO2 ,4-NO2 , 4-F, 4-Br, 4-CH3,
4-(CH3)2N, 2-CH3, 3-CH3).
N
H
N
O
Br
O
O CH3
N
H
N
O
Br
O
O CH3
Figure 14:
N
N
O
O
O
H
OR3
R3O
R3O
R1
R2
N
N
O
O
O
H
OR3
R3O
R3O
R1
R2
P confirmation M confirmation
Figure 15: R1=CH3, H R2= Cl, Br, NO2, NH2 R3= OH, O-benzyl.
N
N
R1
N
R2
R
Figure 16: R=COOC2H5, COONH2, CN, R1=H, F, Cl, R2= H, F, Cl.