Journal
TROPICAL BIOMEDICINE
Volume 39, Issue 3, Pages 467-475Publisher
MALAYSIAN SOC PARASITOLOGY TROPICAL MEDICINE
DOI: 10.47665/tb.39.3.019
Keywords
2; 5-disubstituted-1; 3; 4-oxadiazoles; anti-mycobacterial; Mycobacterium smegmatis; Mycobacterium tuberculosis H37Ra; molecular docking
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Funding
- Universiti Sains Malaysia USM RUI [1001/PKIMIA/8011072]
- Ministry of Higher Education of Malaysia (MyBrain15 Scheme- MyMaster)
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A series of new 2,5-disubstituted-1,3,4-oxadiazole derivatives have been synthesized and characterized. Compound 5d exhibited the highest antibacterial activity against M. smegmatis and showed good synergy with isoniazid. Docking simulation suggested its potential as a pantothenate synthetase inhibitor.
A series of new 2,5-disubstituted-1,3,4-oxadiazole derivatives (5a-j and 6a-j) have been designed and synthesized in four-steps. Sixteen compounds among the twenty compounds are reported for the first time. The compounds were characterized and confirmed by the FTIR, 1D-and 2D-NMR and HRMS analyses, and were tested against Mycobacterium smegmatis and Mycobacterium tuberculosis H37Ra. Compound 5d was the most active against M. smegmatis with MIC value of 25 mu M, and exhibited cidal activity with MBC of 68 mu M, respectively. The time-kill assay showed the good killing rate at 77% with the combination of isoniazid (INH). In addition, checkboard assay confirmed the interaction of compound 5d was categorised as additive. Docking simulation has been performed to position 5d into the pantothenate synthetase active site with binding free energy value -8.6 kcal mol-1. It also occupied the same active site as that of standard native ligand with similar interactions, which clearly indicate their potential as pantothenate synthetase inhibitor.
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