Synthesis, biological evaluation and molecular modeling study of new (1,2,4-triazole or 1,3,4-thiadiazole)-methylthio-derivatives of quinazolin-4(3 H )-one as DHFR inhibitors

El‐Gazzar, Yomna I.; Georgey, Hanan H.; El‐Messery, Shahenda M.; Ewida, Heba A.; Hassan, Ghada S.; Raafat, Marwa M.; Ewida, Menna A.; El‐Subbagh, Hussein I.

doi:10.1016/j.bioorg.2017.04.019

Cited by 52 publications

(42 citation statements)

References 24 publications

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“…DHFR is an essential enzyme which catalyzes the reduction of dihydrofolate acid (DHF) to tetrahydrofolic acid (THF) using reduced NADPH as a cofactor and plays a major role in the biosynthesis nucleic acids. Therefore, DHFR couples with thymidylate synthase (TS), which catalyzes the reductive methylation of deoxyuridine monophosphate in deoxythymidine monophosphate using N5 -N10-methylenetetrahydrofolate (5,10-Methylene THF) as a cofactor [165][166][167][168]. Despite the extensive targeting of DHFR in pathogenic organisms [153,[169][170][171], hDHFR is also targeted by anticancer agents [172][173][174][175].…”

Section: Dhfr Enzyme As Anticancer Targetmentioning

confidence: 99%

Trimethoprim and other nonclassical antifolates an excellent template for searching modifications of dihydrofolate reductase enzyme inhibitors

Arciszewska²,

et al. 2019

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The development of new mechanisms of resistance among pathogens, the occurrence and transmission of genes responsible for antibiotic insensitivity, as well as cancer diseases have been a serious clinical problem around the world for over 50 years. Therefore, intense searching of new leading structures and active substances, which may be used as new drugs, especially against strain resistant to all available therapeutics, is very important. Dihydrofolate reductase (DHFR) has attracted a lot of attention as a molecular target for bacterial resistance over several decades, resulting in a number of useful agents. Trimethoprim (TMP), (2,4-diamino-5-(3′,4′,5′-trimethoxybenzyl)pyrimidine) is the well-known dihydrofolate reductase inhibitor and one of the standard antibiotics used in urinary tract infections (UTIs). This review highlights advances in design, synthesis, and biological evaluations in structural modifications of TMP as DHFR inhibitors. In addition, this report presents the differences in the active site of human and pathogen DHFR. Moreover, an excellent review of DHFR inhibition and their relevance to antimicrobial and parasitic chemotherapy was presented.

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Section: Dhfr Enzyme As Anticancer Targetmentioning

confidence: 99%

Trimethoprim and other nonclassical antifolates an excellent template for searching modifications of dihydrofolate reductase enzyme inhibitors

Arciszewska²,

et al. 2019

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“…Derivatives of 1,2,4-triazole are actively researched by scientific teams around the world on the ability to manifest a wide range of biological effects [4][5][6]. Thus, in the scientific literature there is available data on their use as antimicrobial, anti-inflammatory, analgesic, antiepileptic, antiviral, antihypertensive, antimalarial, sedative, antihistamines, anti-TB drugs, etc.…”

Section: Introductionmentioning

confidence: 99%

The development of HPLC-DAD method for determination of active pharmaceutical ingredient in the potassium 2-((4-amino-5-(morpholinomethyl)-4H-1,2,4-triazol-3-yl)thio) acetate substance

Shcherbyna

Парченко

Varynskyi

et al. 2019

Current Issues in Pharmacy and Medical Sciences

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Derivatives of 1,2,4-triazole are actively researched by scientists and synthetic pharmacologists. The last studies have shown that potassium 2-((4-amino-5-(morpholinomethyl)-4H-1,2,4-triazol-3-yl)thio)acetate with low toxicity series exhibits antioxidant and hepatoprotective properties. Therefore, the purpose of this work was to develop a method for determining the API in the potassium 2-((4-amino-5-(morpholinomethyl)-4H-1,2,4-triazol-3-yl)thio)acetate substance using the method of high-performance liquid chromatography with diode array detection (HPLC-DAD). As a result of this work, it is shown that the developed method is specific and meets the requirements of linearity, accuracy and precision. The results of determining the contents of the API in real samples indicate that the method can be proposed to control the quality of the potassium 2-((4-amino-5-(morpholinomethyl)-4H-1,2,4-triazol-3-yl)thio)acetate substance.

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“…Several studies showed that triazole analogs can be used as potential DHFR inhibitors . It is a well‐known fact that DHFR is a key enzyme in the folate metabolism.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Characterization, Molecular Modeling, and Biological Evaluation of 1,2,4‐Triazole‐pyridine Hybrids as Potential Antimicrobial Agents

Ahirwar¹,

Ahirwar²,

Lanjhiyana³

et al. 2018

Journal of Heterocyclic Chem

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A novel 1,2,4‐triazole‐pyridine hybrid derivatives were synthesized by the reaction of nicotinohydrazide with carbon disulfide to yield potassium‐3‐pyridyl‐dithiocarbazate (I). This was further cyclized with ammonia solution to yield 5‐mercapto‐substituted 1,2,4‐triazole‐pyridine hybrid (II). This was finally reacted with different substituted benzyl derivatives to produce 1,2,4‐triazole‐pyridine hybrid derivatives (III). The purity of the derivatives was confirmed by thin‐layer chromatography and melting point. Structure of these derivatives was set up by determining its infrared spectroscopy, nuclear magnetic resonance spectroscopy, and mass spectroscopy. Further, the synthesized derivatives were evaluated for their in vitro antimicrobial activity against the three Gram‐negative bacteria (Escherichia coli, Pseudomonas aeruginosa, and Acinetbacter baumannii), three Gram‐positive bacteria (Staphylococcus aureus, Streptococcus pyogenes, and Enterococcus faecalis), and two fungus (Aspergillus clavatus and Candida albicans). Minimal inhibitory concentration was also determined against same microorganism. Out of all synthesized derivatives, two derivatives, that is, 3‐(5‐(2‐bromobenzylthio)‐4H‐1,2,4‐triazol‐3‐yl)pyridine and 3‐(5‐(2,4‐dibromobenzylthio)‐4H‐1,2,4‐triazol‐3‐yl)pyridine showing more potent antibacterial activity. Docking studies were performed by using Argus lab, and all the derivatives exhibited good docking scores between −10.5369 and −11.8477 kcal/mol and were better as compared with standard drug methotrexate against a dihydrofolate reductase protein fragment from E. coli and Lactobacillus (4DFR). Among all compounds, 4h has shown the maximum docking score and found in agreement to in vitro antimicrobial studies.

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Synthesis, biological evaluation and molecular modeling study of new (1,2,4-triazole or 1,3,4-thiadiazole)-methylthio-derivatives of quinazolin-4(3 H )-one as DHFR inhibitors

Cited by 52 publications

References 24 publications

Trimethoprim and other nonclassical antifolates an excellent template for searching modifications of dihydrofolate reductase enzyme inhibitors

Trimethoprim and other nonclassical antifolates an excellent template for searching modifications of dihydrofolate reductase enzyme inhibitors

The development of HPLC-DAD method for determination of active pharmaceutical ingredient in the potassium 2-((4-amino-5-(morpholinomethyl)-4H-1,2,4-triazol-3-yl)thio) acetate substance

Synthesis, Characterization, Molecular Modeling, and Biological Evaluation of 1,2,4‐Triazole‐pyridine Hybrids as Potential Antimicrobial Agents

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