<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>

Abstract

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.

Investigation of Antifungal Properties of Synthetic Dimethyl-4-Bromo-1-(Substituted Benzoyl) Pyrrolo[1,2-a] Quinoline-2,3-Dicarboxylates Analogues: Molecular Docking Studies and Conceptual DFT-Based Chemical Reactivity Descriptors and Pharmacokinetics Evaluation

“…However, in organic chemistry, the maximum heterocyclic compounds possess significant biological activity [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. Recent reports suggest that indolizine is a very attractive molecule among the heterocyclic compounds and possesses two fused ring structures with carbon and nitrogen bridging atoms.…”

“…Recent reports suggest that indolizine is a very attractive molecule among the heterocyclic compounds and possesses two fused ring structures with carbon and nitrogen bridging atoms. Further, the numerous indolizine derivatives show potential biological activities [ 16 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ], which includes antioxidant [ 42 , 43 , 44 ], antimicrobial [ 42 , 43 , 44 , 45 , 46 ], anti-inflammatory [ 47 ], anticancer [ 48 , 49 ] and antituberculosis [ 50 ] activities.…”

Cytotoxicity and Antimycobacterial Properties of Pyrrolo[1,2-a]quinoline Derivatives: Molecular Target Identification and Molecular Docking Studies

“…In addition, the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains, which are highly resistant to most of the currently available anti-TB drugs, trigger the urgent need for the development of novel therapeutic agents to combat these resistant strains [3,4] as only a few drugs are available with United States Food and Drug Administration (US FDA) approval ( Figure 1). Reviews focused on Mycobacterium tuberculosis and in the pursuit of developing novel anti-TB agents, we recently launched a medicinal chemistry program aimed at developing novel, natural [5], cyclic depsipeptides [6] and various heterocyclic scaffolds as potential anti-TB agents [7][8][9][10][11][12][13], including analogues of indolizine such as pyrrolo [1,2-a]quinoline and pyrrolo [1,2-a]isoquinoline, also known as 5,6-benzo-fused indolizine and 7,8-benzo-fused indolizine, respectively [14]. These scaffolds have attracted the attention of medical chemists, as they exhibit a wide variety of pharmacological properties [15].…”

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

“…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].…”

“…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 ].…”