Microwave-assisted synthesis, molecular docking and antitubercular activity of 1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives

Mohan, Sahoo Biswa; Kumar, B. V. V. Ravi; Dinda, Subas Chandra; Naik, D.; Subbiah, Seenivasan; Kumar, Vanaja; Rana, Dharmarajsinh N.; Brahmkshatriya, Pathik S.

doi:10.1016/j.bmcl.2012.10.032

Cited by 30 publications

(18 citation statements)

References 14 publications

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“…However, mutations in KatG/EthA have been reported and correlated with the development of Mtb resistance to INH and ETH [31,32], thus leading to the need for new molecules that can either directly inhibit the InhA enzyme or find novel molecular paths that can ultimately promote bacterium eradication. Within the 46 manuscripts, the Enoyl-[acyl-carrier-protein] reductase (NADH) (EC 1.3.1.9) was evaluated nine times [10,15,33,34,35,36,37,38,39]. All analyzed articles were able to correctly dock their postulated inhibitors on different sites of the enzyme and studied the obtained results with in vitro assays.…”

Section: Resultsmentioning

confidence: 99%

Predictive Power of In Silico Approach to Evaluate Chemicals against M. tuberculosis: A Systematic Review

et al. 2019

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Mycobacterium tuberculosis (Mtb) is an endemic bacterium worldwide that causes tuberculosis (TB) and involves long-term treatment that is not always effective. In this context, several studies are trying to develop and evaluate new substances active against Mtb. In silico techniques are often used to predict the effects on some known target. We used a systematic approach to find and evaluate manuscripts that applied an in silico technique to find antimycobacterial molecules and tried to prove its predictive potential by testing them in vitro or in vivo. After searching three different databases and applying exclusion criteria, we were able to retrieve 46 documents. We found that they all follow a similar screening procedure, but few studies exploited equal targets, exploring the interaction of multiple ligands to 29 distinct enzymes. The following in vitro/vivo analysis showed that, although the virtual assays were able to decrease the number of molecules tested, saving time and money, virtual screening procedures still need to develop the correlation to more favorable in vitro outcomes. We find that the in silico approach has a good predictive power for in vitro results, but call for more studies to evaluate its clinical predictive possibilities.

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Section: Resultsmentioning

confidence: 99%

Predictive Power of In Silico Approach to Evaluate Chemicals against M. tuberculosis: A Systematic Review

et al. 2019

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“…63–69 In contrast, some pioneering VS against InhA have yielded predictions that were experimentally validated with enzyme inhibition assays 70 and/or whole-cell growth assays against Mtb , 71, 72 M. vanbaalenii , 73 or M. smegmatis . 74 These previous, experimentally validated VS against InhA helped establish the feasibility of computer-aided drug discovery against this system and laid the foundation for the research we present.…”

Section: Introductionmentioning

confidence: 99%

A Virtual Screen Discovers Novel, Fragment-Sized Inhibitors ofMycobacterium tuberculosisInhA

Perryman

Wang

et al. 2015

J. Chem. Inf. Model.

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Isoniazid (INH) is usually administered to treat latent Mycobacterium tuberculosis (Mtb) infections, and is used in combination therapy to treat active tuberculosis disease (TB). Unfortunately, resistance to this drug is hampering its clinical effectiveness. INH is a prodrug that must be activated by Mtb catalase peroxidase (KatG) before it can inhibit InhA (Mtb enoyl-acyl-carrier-protein reductase). Isoniazid-resistant cases of TB found in clinical settings usually involve mutations in or deletion of katG, which abrogate INH activation. Compounds that inhibit InhA without requiring prior activation by KatG would not be affected by this resistance mechanism and hence would display continued potency against these drug-resistant isolates of Mtb. Virtual screening experiments versus InhA in the GO Fight Against Malaria project (GO FAM) were designed to discover new scaffolds that display base stacking interactions with the NAD cofactor. GO FAM experiments included targets from other pathogens, including Mtb, when they had structural similarity to a malaria target. Eight of the sixteen soluble compounds identified by docking against InhA plus visual inspection were modest inhibitors and did not require prior activation by KatG. The best two inhibitors discovered are both fragment-sized compounds and displayed Ki values of 54 and 59 μM, respectively. Importantly, the novel inhibitors discovered have low structural similarity to known InhA inhibitors and, thus, help expand the number of chemotypes on which future medicinal chemistry efforts can be focused. These new fragment hits could eventually help advance the fight against INH-resistant Mtb strains, which pose a significant global health threat.

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“…17,18 Various drugs containing pyrimidine nucleus were synthesized and used as anticancer agents like 5-fluorouracil (5-FU), tegafur and thioguanine ( Figure 1). 19 In recent years dihydropyrimidinones/thiones (DHPMs) and their derivatives have occupied an important position in natural and synthetic organic chemistry because of their wide range of biological activities, such as antioxidant, antiinflammatory, anthelminic, antimicrobial, [20][21][22] antituberculoses 23 and anticancer. 24 Although a number of papers have been concerned with the synthesis of pyrimidine derivatives, 17,18 just a few one pot syntheses have been published using aromatic aldehydes, ethyl cyanoacetate and thiourea.…”

Section: Introductionmentioning

confidence: 99%

“…24 Although a number of papers have been concerned with the synthesis of pyrimidine derivatives, 17,18 just a few one pot syntheses have been published using aromatic aldehydes, ethyl cyanoacetate and thiourea. 11,[20][21][22][23][24] Also, it was reported that 3,4-dihydropyrimidinone/thione have been synthesized by a three-component condensation of aldehydes, ethyl acetoacetate and urea/thiourea using different catalysts and new methods to improve and modify this reaction. [25][26][27][28][29] Moreover, the one step synthesis of 6-amino-5-cyano-4-phenyl-2-mercaptopyrimidine using aldehydes, malononitrile and urea/thiourea in the presence of a catalytic amount of phosphorus pentoxide has been reported.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antitumor Evaluation of Novel Dihydropyrimidine, Thiazolo[3,2-a]Pyrimidine and Pyrano[2,3-d]Pyrimidine Derivatives

Abdo¹

2015

ACSi

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A simple and efficient method has been developed for the synthesis of 4,5-dihydro-2-mercapto-4-oxo-6-substituted arylpyrimidine derivatives 2a-e and their fused rings 3b, 4b, 5b, 6b and also 1,4-dihydro-2-mercaptopyrimidine derivatives 7a-e, 9a-e using triethylamine as a catalyst. The structure of the newly synthesized compounds was confirmed on the basis of their spectral data and elemental analyses. All the synthesized compounds were evaluated for their in vitro anticancer activity against six human cancer cell lines and normal fibroblasts. Nine of the tested compounds (i.e. 2a, 2c, 2d, 3b, 4b, 5b, 8, 9a and 9c) exhibited significant cytotoxicity against most cell lines. Among these derivatives compounds 2a, 3b and 9c are the most potent, they exhibited cytotoxic effect against the six cancer cell lines with IC 50 values < 330 nM compared to the standard CHS 828. Normal fibroblast cells (WI38) were affected to a much lesser extent (IC 50 >10,000 nM). Toxicity of the most potent compounds was measured against shrimp larvae; the results showed that compounds 2a and 3b are not toxic towards the tested organisms.

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Microwave-assisted synthesis, molecular docking and antitubercular activity of 1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives

Cited by 30 publications

References 14 publications

Predictive Power of In Silico Approach to Evaluate Chemicals against M. tuberculosis: A Systematic Review

Predictive Power of In Silico Approach to Evaluate Chemicals against M. tuberculosis: A Systematic Review

A Virtual Screen Discovers Novel, Fragment-Sized Inhibitors ofMycobacterium tuberculosisInhA

Synthesis and Antitumor Evaluation of Novel Dihydropyrimidine, Thiazolo[3,2-a]Pyrimidine and Pyrano[2,3-d]Pyrimidine Derivatives

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