Development of selective DprE1 inhibitors: Design, synthesis, crystal structure and antitubercular activity of benzothiazolylpyrimidine-5-carboxamides

Chikhale, Rupesh; Menghani, Sunil; Babu, R. Satheesh; Bansode, Ratnadeep; Bhargavi, G.; Karodia, Nazira; Rajasekharan, M. V.; Paradkar, Anant; Khedekar, Pramod B.

doi:10.1016/j.ejmech.2015.04.011

Cited by 95 publications

(39 citation statements)

References 29 publications

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“…In order to investigate the molecular interactions and binding modes of some of the synthesized derivatives like 50, 51, 53, 55 and 62, we docked these derivatives with COX enzyme (PDB code 4Z0L) 29 using licensed version of Vlife MDS 4.32 software tools. 22 This COX-2 receptor was used for our study because of two reasons: first, this complex provides with a indole derivative, which can act as a reference molecule for docking; and the second reason was the similarity with our animal model. Prior to carrying out docking the COX-2 receptor was prepared for docking by removing the ligands in complex but the water molecules were retained for this particular study.…”

Section: Resultsmentioning

confidence: 99%

“…29 The receptor molecule was refined and validated on the basis of Ramchandran plot using Biopredicta© module on the Vlife MDS Molecular Modeling software, version 4.3.1. 22 The Vlife MDS suit uses k-nearest neighbour genetic algorithm (KNN-GA) method for molecular docking. 22 The scoring function is based on the basis of best suited moiety for the target with respect to energy and inter molecular interactions.…”

Section: Molecular Docking Studymentioning

confidence: 99%

“…22 The Vlife MDS suit uses k-nearest neighbour genetic algorithm (KNN-GA) method for molecular docking. 22 The scoring function is based on the basis of best suited moiety for the target with respect to energy and inter molecular interactions. The ligands that were already present within the receptor in bound form were removed to allow for docking protocol.…”

Section: Molecular Docking Studymentioning

confidence: 99%

“…This was achieved by molecular docking studies of the ligands on the COX-II receptor. 22,23 The series of final derivatives N'-(2-oxoindolin-3-ylidene)-3-(5-substituted phenyl-1,3,4-oxadiazol-2-yl) propane hydrazides 49-63 as described in this study is outlined in Scheme 1. The products were obtained following two different steps; in the first step various substituted benzoic acids 1-15 were obtained commercially; these substituents were reacted with ethanol in presence of sulphuric acid to derive corresponding benzoates 16-30 under conditions of nucleophilic substitution reaction.…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis, Pharmacological Evaluation and Molecular Docking Studies of Substituted Oxadiazolyl-2-Oxoindolinylidene Propane Hydrazide Derivatives

Kerzare¹,

Chikhale²,

Bansode³

et al. 2016

Journal of the Brazilian Chemical Society

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The manuscript describes design and synthesis of novel oxadiazolyl-2-oxoindolinylidene propane hydrazides as amide tethered hybrids of indole and oxadiazole and their evaluation for antiinflammatory and analgesic activity. The compounds were synthesized following five step reaction to yield fifteen derivatives as 3- (5-propane hydrazide and 3-[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]-N'-[2-oxo-1,2-dihydro-3H-indol-3-ylidene]propane hydrazide were found to be highly promising molecules with severity index of 0.35 and 0.56, respectively, which is promising for an analgesic compound. The hydroxy and methyl substitution on phenyl ring system provided with active anti-inflammatory compounds having increase in reaction time of 84.11 and 83.17%, respectively compared to standard drug at 85.84%. Molecular docking studies exhibit comparable interaction with synthesized derivatives and standard drug having a dock score of −4.44 by the K-nearest neighbour genetic algorithm method.

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Section: Resultsmentioning

confidence: 99%

Section: Molecular Docking Studymentioning

confidence: 99%

Section: Molecular Docking Studymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis, Pharmacological Evaluation and Molecular Docking Studies of Substituted Oxadiazolyl-2-Oxoindolinylidene Propane Hydrazide Derivatives

Kerzare¹,

Chikhale²,

Bansode³

et al. 2016

Journal of the Brazilian Chemical Society

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“…The compounds were designed as selective DprE1 inhibitors. The most promising analogues 32 exhibits MICs ranged in 0.08–0.09 μM, and displayed selective inhibition of DprE1 (IC 50 = 7.7–11.1 μM) …”

Section: Benzothiazolesmentioning

confidence: 99%

New structural classes of antituberculosis agents

Kumar

Patel

Jain

2017

Medicinal Research Reviews

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Tuberculosis (TB), one of the deadliest diseases is shattering the health and socioeconomic status of the society. The emergence of multidrug resistant (MDR) and extremely drug resistant (XDR) strains has provided unprecedented lethal character to TB. The development of MDR and XDR strains of TB results in more deaths, longer duration of therapy, and appearance of the disease in the immunocompromised patients. Because of the development of rapid resistance by Mycobacterium tuberculosis, researchers are confronted with serious challenges in combating TB. For instance, the need for potency and specificity in therapeutic agents approaching clinics, and the increasing demand of low toxicity due to long duration of treatment. Recently, it is proposed that such challenges could be addressed by a shift from contemporary or known classes of drugs to new scaffold-containing or entirely new structural classes of drugs that possibly act on the previously unknown targets, resulting in possibly less instances of resistance development. The exploitation of advances made in the biology of TB in the last and present decades have created opportunities to discover a large number of new structural classes that specifically targets TB by molecular mechanism of action(s) unknown earlier. We have earlier reviewed new structural classes of anti-TB agents up to year 2005. This review covers literature reports of the subsequent 10 years on the discovery of new structural classes of synthetic anti-TB agents. Due to the availability of large number of research reports, we have divided new compounds in 38 structural classes, 368 structures, and 307 references.

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In silico molecular docking studies of oxadiazole and pyrimidine bearing heterocyclic compounds as potential antimicrobial agents

Desai

Vaghani

Jethawa

et al. 2021

Archiv der Pharmazie

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Microbial resistance is a major problem faced by the scientific community. It has created an urgent need to develop antimicrobial agents with novel structures and mechanisms of action. With this aim, a series of novel 1,3,4‐oxadiazoles bearing 3,4‐dihydropyrimidine heterocyclic motifs 4a–l were designed and synthesized. One‐pot Biginelli synthesis is pivotal due to the use of readily available chemicals, shorter reaction time, and ecofriendly synthesis with a good yield. The structures of the synthesized molecules were characterized and confirmed by infrared, 1H nuclear magnetic resonance (NMR), 13C NMR, and mass spectroscopic techniques. The title compounds were screened against Gram‐positive and ‐negative strains of bacteria and fungi using the Mueller–Hinton broth method. Compound 4d was found to be the most promising against Escherichia coli (12.5 µg/ml), whereas the same compound showed good activity against Staphylococcus aureus at a concentration of 50 µg/ml. Other compounds of the same series, 4c and 4h, displayed moderate activity against Streptococcus pyogenes at a concentration of 50 µg/ml. Furthermore, results of the antifungal activity tests revealed that compound 4i showed promising activity against all the strains of fungi, Candida albicans, Aspergillus niger, and Aspergillus clavatus, at concentrations of 100, 50, and 100 µg/ml, respectively. Molecular docking also showed that these compounds had a significant binding affinity (Glide docking score: −7.74 to −6.531) for DNA gyrase, engaging in a series of bonded and nonbonded interactions with residues lining the active site. The results of molecular docking study validated the experimental findings, thereby providing an initiation mark to optimize this motif using a structure‐based drug design approach.

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Development of selective DprE1 inhibitors: Design, synthesis, crystal structure and antitubercular activity of benzothiazolylpyrimidine-5-carboxamides

Cited by 95 publications

References 29 publications

Design, Synthesis, Pharmacological Evaluation and Molecular Docking Studies of Substituted Oxadiazolyl-2-Oxoindolinylidene Propane Hydrazide Derivatives

Design, Synthesis, Pharmacological Evaluation and Molecular Docking Studies of Substituted Oxadiazolyl-2-Oxoindolinylidene Propane Hydrazide Derivatives

New structural classes of antituberculosis agents

In silico molecular docking studies of oxadiazole and pyrimidine bearing heterocyclic compounds as potential antimicrobial agents

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