Novel pyrazine based anti-tubercular agents: Design, synthesis, biological evaluation and in silico studies
| Autor: | Dharmarajan Sriram, Yasser S. Abdel-Ghany, Perihan A. Elzahhar, Soad A.M. El-Hawash, Rasha A. Nassra, Manal N. S. Saudi, Nayera W. Hassan, Marwa M. Abdel-Aziz, Azza Ismail |
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| Rok vydání: | 2020 |
| Předmět: |
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Molecular Pyrazine In silico Antitubercular Agents Microbial Sensitivity Tests 01 natural sciences Biochemistry Madin Darby Canine Kidney Cells Structure-Activity Relationship chemistry.chemical_compound Dogs Drug Discovery Animals Humans Tuberculosis Computer Simulation MTT assay Molecular Biology chemistry.chemical_classification biology 010405 organic chemistry Organic Chemistry Active site Mycobacterium tuberculosis In vitro 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Enzyme chemistry Docking (molecular) Pyrazines biology.protein Caco-2 Cells Pharmacophore |
| Zdroj: | Bioorganic Chemistry. 96:103610 |
| ISSN: | 0045-2068 |
| DOI: | 10.1016/j.bioorg.2020.103610 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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