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Title: Design, synthesis and molecular docking studies of quinazolin-4-ones linked to 1,2,3-triazol hybrids as Mycobacterium tuberculosis H{sub 37}Rv inhibitors besides antimicrobial activity

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 CuSO{sub 4} under aerobic conditions followed by click reaction with substituted aldehydes. The target compounds were screened for antitubercular activity against Mycobacterium tuberculosis H{sub 37}Rv 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 H{sub 37}Rv 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 amore » 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).« less

Authors:
;  [1];  [2]; ;  [3]; ;  [2]
  1. Koneru Lakshmaiah Education Foundation (KLEF), Green Fields, Vaddeswaram, Department of Chemistry (India)
  2. Andhra University, Department of Organic Chemistry (India)
  3. Genome valley, Shamirpet, Turkapally village, Medchal District, United States Pharmacopeia India Pvt. Ltd., IKP Knowledge Park (India)
Publication Date:
OSTI Identifier:
22936202
Resource Type:
Journal Article
Journal Name:
Medicinal Chemistry Research (Print)
Additional Journal Information:
Journal Volume: 28; Journal Issue: 4; Other Information: Copyright (c) 2019 Springer Science+Business Media, LLC, part of Springer Nature; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 1054-2523
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AEROBIC CONDITIONS; ALDEHYDES; ALKYNES; AMINO ACIDS; ANTIBIOTICS; BENZENE; COPPER SULFATES; LIGASES; MYCOBACTERIUM TUBERCULOSIS; TRIAZOLES

Citation Formats

Maddali, Narendra Kumar, Viswanath, I. V. Kasi, Murthy, Y. L. N.,, Bera, Rabin, Takhi, Mohamed, Rao, Nethinti Sundara, and Gudla, Vanajakshi. Design, synthesis and molecular docking studies of quinazolin-4-ones linked to 1,2,3-triazol hybrids as Mycobacterium tuberculosis H{sub 37}Rv inhibitors besides antimicrobial activity. United States: N. p., 2019. Web. doi:10.1007/S00044-019-02313-9.
Maddali, Narendra Kumar, Viswanath, I. V. Kasi, Murthy, Y. L. N.,, Bera, Rabin, Takhi, Mohamed, Rao, Nethinti Sundara, & Gudla, Vanajakshi. Design, synthesis and molecular docking studies of quinazolin-4-ones linked to 1,2,3-triazol hybrids as Mycobacterium tuberculosis H{sub 37}Rv inhibitors besides antimicrobial activity. United States. https://doi.org/10.1007/S00044-019-02313-9
Maddali, Narendra Kumar, Viswanath, I. V. Kasi, Murthy, Y. L. N.,, Bera, Rabin, Takhi, Mohamed, Rao, Nethinti Sundara, and Gudla, Vanajakshi. 2019. "Design, synthesis and molecular docking studies of quinazolin-4-ones linked to 1,2,3-triazol hybrids as Mycobacterium tuberculosis H{sub 37}Rv inhibitors besides antimicrobial activity". United States. https://doi.org/10.1007/S00044-019-02313-9.
@article{osti_22936202,
title = {Design, synthesis and molecular docking studies of quinazolin-4-ones linked to 1,2,3-triazol hybrids as Mycobacterium tuberculosis H{sub 37}Rv inhibitors besides antimicrobial activity},
author = {Maddali, Narendra Kumar and Viswanath, I. V. Kasi and Murthy, Y. L. N., and Bera, Rabin and Takhi, Mohamed and Rao, Nethinti Sundara and Gudla, Vanajakshi},
abstractNote = {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 CuSO{sub 4} under aerobic conditions followed by click reaction with substituted aldehydes. The target compounds were screened for antitubercular activity against Mycobacterium tuberculosis H{sub 37}Rv 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 H{sub 37}Rv 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).},
doi = {10.1007/S00044-019-02313-9},
url = {https://www.osti.gov/biblio/22936202}, journal = {Medicinal Chemistry Research (Print)},
issn = {1054-2523},
number = 4,
volume = 28,
place = {United States},
year = {2019},
month = {4}
}