Synthesis and Structural Elucidation of Novel Benzothiazole Derivatives as Anti-tubercular Agents: In-silico Screening for Possible Target Identification

Venugopala, Katharigatta N.; Chandrashekharappa, Sandeep; Pillay, Melendhran; Bhandary, Subhrajyoti; Kandeel, Mahmoud; Mahomoodally, Fawzi M.; Morsy, Mohamed A.; Chopra, Deepak; Al‐Dhubiab, Bandar E.; Attimarad, Mahesh; Alwassil, Osama I.; Harsha, Sree; Mlisana, Koleka; Odhav, Bharti

doi:10.2174/1573406414666180703121815

Cited by 45 publications

(28 citation statements)

References 33 publications

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“…MD simulation has been used to reveal structural changes in proteins and enzymes in response to various ligands or protein-protein interactions [25,26]. By utilizing MD technique, structural dynamic changes that cannot be easily handled by other experimental techniques can be evaluated.…”

Section: Discussionmentioning

confidence: 99%

Molecular dynamics simulation of carbonyl reductase 1 clarifies the structural switch in drug metabolism

Kandeel

Alzahrani

2020

Journal of Taibah University for Science

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Carbonyl reductase 1 (CBR1), a short-chain dehydrogenase/reductase, is important in the phase I reduction of drugs. Glutathione (GSH) facilitates the access of low-affinity substrates to the CBR1 active site. This study investigates the path of substrates to the CBR1 active site when GSH occludes the entrance to NADP and binds its catalytic residues. A set of CBR1 structures bound with GSH were subjected to comprehensive docking and molecular dynamics (MD) simulations. The glycine moiety of GSH dangled within the active site, converting the active site into ON/OFF status, while the glutamate residue slips into a hydrophobic cavity, allowing more room for driving the substrate toward the active residues. GSH spontaneously moves within the apoCBR1 binding site and acts as an internal control barrier that selects substrates entering the catalytic site. The VAL230-TYR251 was most flexible in ApoCBR1 structure and showed a lower degree of flexibility upon the binding of inhibitors.

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Section: Discussionmentioning

confidence: 99%

Molecular dynamics simulation of carbonyl reductase 1 clarifies the structural switch in drug metabolism

Kandeel

Alzahrani

2020

Journal of Taibah University for Science

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“…Antibiotics 2020, 9, x FOR PEER REVIEW 3 of 17 5-(4-fluoro-3-phenoxyphenyl)-4H-1,2,4-triazole-3-thiol (1) and its Schiff bases 2, 3 and 4 be tested for their whole-cell anti-TB activity against H37Rv and MDR strains of M. tuberculosis, which is resistant to treatment with rifampicin and isoniazid (1 and 0.2 µg/mL, respectively), as determined by resazurin microtiter assay (REMA) plate method. Due to the urgent call for novel scaffolds as anti-TB agents, we have recently launched a medicinal chemistry program aimed at developing novel, natural [37], cyclic depsipeptides [38] and heterocyclic scaffolds as potential anti-TB agents [39][40][41][42][43][44][45][46][47]. A new scaffold of triazole thiols produced antibacterial effects by targeting folate synthesis via bacterial dihydrofolate reductase [48].…”

Section: Introductionmentioning

confidence: 99%

Anti-Tubercular Properties of 4-Amino-5-(4-Fluoro-3- Phenoxyphenyl)-4H-1,2,4-Triazole-3-Thiol and Its Schiff Bases: Computational Input and Molecular Dynamics

et al. 2020

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In the present investigation, the parent compound 4-amino-5-(4-fluoro-3-phenoxyphenyl)-4H-1,2,4-triazole-3-thiol (1) and its Schiff bases 2, 3, and 4 were subjected to whole-cell anti-TB against H37Rv and multi-drug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB) by resazurin microtiter assay (REMA) plate method. Test compound 1 exhibited promising anti-TB activity against H37Rv and MDR strains of MTB at 5.5 µg/mL and 11 µg/mL, respectively. An attempt to identify the suitable molecular target for compound 1 was performed using a set of triazole thiol cellular targets, including β-ketoacyl carrier protein synthase III (FABH), β-ketoacyl ACP synthase I (KasA), CYP121, dihydrofolate reductase, enoyl-acyl carrier protein reductase, and N-acetylglucosamine-1-phosphate uridyltransferase. MTB β-ketoacyl ACP synthase I (KasA) was identified as the cellular target for the promising anti-TB parent compound 1 via docking and molecular dynamics simulation. MM(GB/PB)SA binding free energy calculation revealed stronger binding of compound 1 compared with KasA standard inhibitor thiolactomycin (TLM). The inhibitory mechanism of test compound 1 involves the formation of hydrogen bonding with the catalytic histidine residues, and it also impedes access of fatty-acid substrates to the active site through interference with α5–α6 helix movement. Test compound 1-specific structural changes at the ALA274–ALA281 loop might be the contributing factor underlying the stronger anti-TB effect of compound 1 when compared with TLM, as it tends to adopt a closed conformation for the access of malonyl substrate to its binding site.

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“…[34][35][36] Herein, we report the anti-TB activity of THP derivatives against H37Rv and multidrug-resistant (MDR) strains of MTB. On the basis of our previous findings on the promising anti-TB activity of THP scaffolds 27,28 on whole-cell anti-TB properties and in a continuous effort to identify novel heterocyclic scaffolds that demonstrate potential anti-TB activity, [37][38][39][40] we screened six 1,2,3,4-tetrahydropyrimidinone (1a-d) and 1,2,3,4-tetrahydropyrimidinethione (2a-b) analogues (Scheme 1) for whole-cell anti-TB activity against H37Rv and MDR strains of MTB by the resazurin microplate assay (REMA) plate method.…”

Section: Introductionmentioning

confidence: 99%

<p>In silico Design and Synthesis of Tetrahydropyrimidinones and Tetrahydropyrimidinethiones as Potential Thymidylate Kinase Inhibitors Exerting Anti-TB Activity Against <em>Mycobacterium tuberculosis</em></p>

Venugopala¹,

Tratrat²,

Pillay³

et al. 2020

DDDT

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Background and Purpose: Tuberculosis has been reported to be the worldwide leading cause of death resulting from a sole infectious agent. The emergence of multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis has made the battle against the infection more difficult since most currently available therapeutic options are ineffective against these resistant strains. Therefore, novel molecules need to be developed to effectively treat tuberculosis disease. Preliminary docking studies revealed that tetrahydropyrimidinone derivatives have favorable interactions with the thymidylate kinase receptor. In the present investigation, we report the synthesis and the mycobacterial activity of several pyrimidinones and pyrimidinethiones as potential thymidylate kinase inhibitors. Methods: The title compounds (1a-d) and (2a-b) were synthesized by a one-pot three-component Biginelli reaction. They were subsequently characterized and used for whole-cell anti-TB screening against H37Rv and multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB) by the resazurin microplate assay (REMA) plate method. Molecular modeling was conducted using the Accelry's Discovery Studio 4.0 client program to explain the observed bioactivity of the compounds. The pharmacokinetic properties of the synthesized compounds were predicted and analyzed. Results: Of the compounds tested for anti-TB activity, pyrimidinone 1a and pyrimidinethione 2a displayed moderate activity against susceptible MTB H37Rv strains at 16 and 32 µg/mL, respectively. Only compound 2a was observed to exert modest activity at 128 µg/mL against MTB strains with cross-resistance to rifampicin and isoniazid. The presence of the trifluoromethyl group was essential to retain the inhibitory activity of compounds 1a and 2a. Molecular modeling studies of these compounds against thymidylate kinase targets demonstrated a positive correlation between the bioactivity and structure of the compounds. The in-silico ADME (absorption, distribution, metabolism, and excretion) prediction indicated favorable pharmacokinetic and drug-like properties for most compounds. Conclusion: Pyrimidinone 1a and pyrimidinethione 2a were identified as the leading compounds and can serve as a starting point to develop novel anti-TB therapeutic agents.

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Synthesis and Structural Elucidation of Novel Benzothiazole Derivatives as Anti-tubercular Agents: In-silico Screening for Possible Target Identification

Cited by 45 publications

References 33 publications

Molecular dynamics simulation of carbonyl reductase 1 clarifies the structural switch in drug metabolism

Molecular dynamics simulation of carbonyl reductase 1 clarifies the structural switch in drug metabolism

Anti-Tubercular Properties of 4-Amino-5-(4-Fluoro-3- Phenoxyphenyl)-4H-1,2,4-Triazole-3-Thiol and Its Schiff Bases: Computational Input and Molecular Dynamics

<p>In silico Design and Synthesis of Tetrahydropyrimidinones and Tetrahydropyrimidinethiones as Potential Thymidylate Kinase Inhibitors Exerting Anti-TB Activity Against <em>Mycobacterium tuberculosis</em></p>

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