Computational, crystallographic studies, cytotoxicity and anti-tubercular activity of substituted 7-methoxy-indolizine analogues

Venugopala, Katharigatta N.; Chandrashekharappa, Sandeep; Pillay, Melendhran; Abdallah, Hassan H.; Mahomoodally, Fawzi M.; Bhandary, Subhrajyoti; Chopra, Deepak; Attimarad, Mahesh; Al‐Dhubiab, Bandar E.; Nair, Anroop B.; Sreeharsha, Nagaraja; Morsy, Mohamed A.; Shinu, Pottathil; Venugopala, Rashmi; Odhav, Bharti; Mlisana, Koleka

doi:10.1371/journal.pone.0217270

Cited by 32 publications

(26 citation statements)

References 35 publications

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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%

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

Venugopala¹,

Tratrat²,

Pillay³

et al. 2020

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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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Section: Introductionmentioning

confidence: 99%

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

Venugopala¹,

Tratrat²,

Pillay³

et al. 2020

DDDT

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“…The indolizine core is present in many biologically active compounds and can be considered an important scaffold for the preparation of new pharmaceuticals [20,21]. These class of compounds holds valuable biologic activities [21], such as antimicrobial [22,23], antioxidant [24,25], anticancer [26][27][28], enzyme inhibitors [29,30], anti-inflammatory [21] and anti-HIV-1 [31]. Consequently, different pathways were described in the literature for their synthesis [32][33][34].…”

Section: Of 16mentioning

confidence: 99%

Whole-Cells of Yarrowia lipolytica Applied in “One Pot” Indolizine Biosynthesis

et al. 2020

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A series of yeast strains was tested in order to evaluate their catalytic potential in biocatalysis of one-pot indolizine’s synthesis. Yeast cultivation was performed in a submerged system at 28 °C for 72 h at 180 rpm. An assessment of the reagents’ toxicity on yeast viability and metabolic functionality concluded that the growth potential of three Yarrowia lipolytica strains were least affected by the reactants compared to the other yeast strains. Further, crude fermentation products (biomass and cell-free supernatant)—obtained by submerged cultivation of these yeasts—were used in multistep cascade reactions for the production of fluorescent indolizine compounds with important biologic activities. A whole–cell catalyzed multicomponent reaction of activated alkynes, α-bromo-carbonyl reagents and 4,4′-bipyridine, at room temperature in buffer solution led to the efficient synthesis of bis-indolizines 4a, 4b and 4c, in good-to-excellent yields (47%–77%). The metabolites of the selected Y. lipolytica strains can be considered effective biocatalysts in cycloaddition reactions and the high purity and bioconversion yields of the synthesized indolizines indicates a great potential of this type of “green” catalysts. Seeds of Triticum estivum L. were used to investigate the impact of the final products on the germination and seedling growth. The most sensitive physiological parameters suggest that indolizines, at the concentrations tested, have non-toxic effect on germination and seedling growth of wheat, fact also confirmed by confocal laser scanning microscopy images.

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“…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].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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A series of ethyl 1-(substituted benzoyl)-5-methylpyrrolo[1,2-a]quinoline-3-carboxylates 4a–f and dimethyl 1-(substituted benzoyl)-5-methylpyrrolo[1,2-a]quinoline-2,3-dicarboxylates 4g–k have been synthesized and evaluated for their anti-tubercular (TB) activities against H37Rv (American Type Culture Collection (ATCC) strain 25177) and multidrug-resistant (MDR) strains of Mycobacterium tuberculosis by resazurin microplate assay (REMA). Molecular target identification for these compounds was also carried out by a computational approach. All test compounds exhibited anti-tuberculosis (TB) activity in the range of 8–128 µg/mL against H37Rv. The test compound dimethyl-1-(4-fluorobenzoyl)-5-methylpyrrolo[1,2-a]quinoline-2,3-dicarboxylate 4j emerged as the most promising anti-TB agent against H37Rv and multidrug-resistant strains of Mycobacterium tuberculosis at 8 and 16 µg/mL, respectively. In silico evaluation of pharmacokinetic properties indicated overall drug-likeness for most of the compounds. Docking studies were also carried out to investigate the binding affinities as well as interactions of these compounds with the target proteins.

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Computational, crystallographic studies, cytotoxicity and anti-tubercular activity of substituted 7-methoxy-indolizine analogues

Cited by 32 publications

References 35 publications

<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>

<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>

Whole-Cells of Yarrowia lipolytica Applied in “One Pot” Indolizine Biosynthesis

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

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