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Design, synthesis and molecular docking studies of quinazolin-4-ones linked to 1,2,3-triazol hybrids as Mycobacterium tuberculosis H37Rv inhibitors besides antimicrobial activity

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Abstract

Quinazolin-4-ones linked to 1,2,3-triazol (10) were identified as inhibitors of the bisphosphonate BPH-700 transcriptional factor from a high throughput screen. A series of 1,4-disubstituted triazoles (10a–j) were synthesized by the Cu-catalyzed azide-alkyne cyclo addition of 5-methoxy-2-nitro-4-(prop-2-yn-1-yloxy) benzamide (6) with various substituted azido benzenes (7) in the presence of CuSO4 under aerobic conditions followed by click reaction with substituted aldehydes. The target compounds were screened for antitubercular activity against Mycobacterium tuberculosis H37Rv by Broth micro dilution method using Lowenstein Jensen medium (LJ) (MIC < 9 μg/mL). Majority of the compounds 10b, 10d, 10e, 10i and 10j displayed good antitubercular activity with MIC 7–11 μg/mL. Further, 10e exhibited a promising inhibition with MIC 7 μg/mL, compared to the reference drug Rifampicin. Docking studies have been performed to understand the interactions between the synthesized compounds and the active site of pantothenate synthetase Mycobacterium tuberculosis H37Rv organism. The study revealed that the target compounds showed good affinity toward the protein when compared to the standard drug Pefloxacin. Further, 10b was found to interact with three amino acids, viz., Gln92, Arg200, Ser196, as evidenced by the large interaction energy (ΔG = −8.16 kcal/mol). Besides the above, the synthesized quinazolinone triazoles 10a–j were evaluated for their antibacterial activities against a panel of Gram +ve and Gram –ve bacteria. Among them 10a, 10e, 10 h and 10j showed promising broad spectrum antibacterial activity with inhibition in the range of 19–33-mm diameter of inhibition zone (DIZ).

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Acknowledgements

The authors are thankful to KLEF (Deemed to be University) management for Ph.D. registration and the management of United States Pharmacopeial Convention for their immense support.

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Authors and Affiliations

  1. Department of Chemistry, Koneru Lakshmaiah Education Foundation (KLEF), Green Fields, Vaddeswaram, Guntur, Andhra Pradesh, 522502, India

    Narendra Kumar Maddali & I. V. Kasi Viswanath*

  2. United States Pharmacopeia India Pvt. Ltd., IKP Knowledge Park, Genome valley, Shamirpet, Turkapally village, Medchal District, Hyderabad, Telangana, 500101, India

    Narendra Kumar Maddali, Rabin Bera & Mohamed Takhi

  3. Department of Organic Chemistry, Andhra University, Visakhapatnam, Andhra Pradesh, 530003, India

    Y. L. N. Murthy*, Nethinti Sundara Rao & Vanajakshi Gudla

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  1. Narendra Kumar Maddali
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  2. I. V. Kasi Viswanath*
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Correspondence to Y. L. N. Murthy*.

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Maddali, N.K., Viswanath*, I.V.K., Murthy*, Y.L.N. et al. Design, synthesis and molecular docking studies of quinazolin-4-ones linked to 1,2,3-triazol hybrids as Mycobacterium tuberculosis H37Rv inhibitors besides antimicrobial activity. Med Chem Res 28, 559–570 (2019). https://doi.org/10.1007/s00044-019-02313-9

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