Novel pyrazine based anti-tubercular agents: Design, synthesis, biological evaluation and in silico studies.

Autor: Hassan NW; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt., Saudi MN; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt., Abdel-Ghany YS; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt., Ismail A; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt., Elzahhar PA; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt., Sriram D; Medicinal Chemistry and Drug Discovery Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Jawahar Nagar, Telangana 500078, India., Nassra R; Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, Egypt., Abdel-Aziz MM; The Regional Center for Mycology and Biotechnology, Al-Azhar University, Cairo 11759, Egypt., El-Hawash SA; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt. Electronic address: Soad.elhawash@alexu.edu.eg.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2020 Mar; Vol. 96, pp. 103610. Date of Electronic Publication: 2020 Jan 25.
DOI: 10.1016/j.bioorg.2020.103610
Abstrakt: TB continues to be a leading health threat despite the availability of powerful anti-TB drugs. We report herein the design and synthesis of various hybrid molecules comprising pyrazine scaffold and various formerly identified anti-mycobacterial moieties. Thirty-one compounds were screened in vitro for their activity against Mycobacterium tuberculosis H37Rv strain using MABA assay. The results revealed that six compounds (8a, 8b, 8c, 8d, 14b and 18) displayed significant activity against Mtb with MIC values ≤6.25 µg/ml versus 6.25 µg/ml for pyrazinamide. The most active compounds were then assessed for their in vitro cytotoxicity against PBMC normal cell line using MTT assay and showed SI > 200. Several in silico studies have been carried out for target fishing of the novel compounds such as shape-based similarity, pharmacophore mapping and inverse docking. Based on this multi-step target fishing study, we suggest that pantothenate synthetase could be the possible target responsible for the action of these compounds. The most active compounds were then successfully docked into the active site of pantothenate synthetase enzyme with favorable binding interactions. In addition, in silico prediction of physicochemical, ADMET and drug-like properties were also determined indicating that compounds 8b, 8c and 8d are promising candidates for the development of new anti-TB agents with enhanced activity and better safety profile.
Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest. The authors alone are responsible for the contents and writing the paper.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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