Design and synthesis of 2-amino-thiophene-proline-conjugates and their anti-tubercular activity against mycobacterium tuberculosis H37Ra

TitleDesign and synthesis of 2-amino-thiophene-proline-conjugates and their anti-tubercular activity against mycobacterium tuberculosis H37Ra
Publication TypeJournal Article
Year of Publication2019
AuthorsBaravkar, SB, Wagh, MA, Nawale, LU, Choudhari, AS, Bhansali, S, Sarkar, D, Sanjayan, GJ
JournalChemistrySelect
Volume4
Issue9
Pagination2851-2857
Date PublishedMAR
Type of ArticleArticle
ISSN2365-6549
Keywords2-aminothiophene, Anti-tubercular, docking studies, Inh A gene, selectivity index
Abstract

The emergence of extensively drug resistant tuberculosis (XDRTB) and multi-drug resistant tuberculosis (MDR-TB) has necessitated the development of new drugs with short chemotherapy treatment regime and cost effectiveness. To overcome these challenges, we are reporting the synthesis of a series of 2-amino-thiophene-proline-conjugates which show potent invino and ex-vivo anti-tubercular (anti-TB) activity against mycobacterium tuberculosis (rntb) H37Ra. The synthesis of these 2-amino-thiophene-proline-conjugates was carried out via solution phase peptide coupling reactions using methyl-2aminothiophene-3-carboxylate 8 as an intermediate obtained by modified gewald reaction. Intermediate 8 was coupled with different amino acids to obtain dipeptides 3, 4, 5, 6a and 7. Priliminary anti-TB assay data encoureaged us to synthesize modified proline derivatives 6b-6k via formation of a benzoxazinone intermediate 16. Most of these conjugates are active against mtb H37Ra in both active (A) and dormant (D) strains. They are also active against drug resistant mtb H37Ra strains. A trifluoroethyl ester analog, 6i was the most potent among the series [MIC 1 mu g/mL] along with 6f and 6g [MIC 2-6 mu g/mL]. Cytotoxicity studies suggested that, these compounds are less cytotoxic to human cell lines HeLa, MCF-7, HUVEC and hence possess high selectivity index (SI). Docking studies revealed that the binding mode of most active compounds 6i, 6g and 6f is in accordance with their bioactivity studies having docking score 8.969, 8.446 and 7.865, respectively. More- over, in sllico ADME properties suggest that all the compounds possess drug like properties.

DOI10.1002/slct.201803370
Type of Journal (Indian or Foreign)

Foreign

Impact Factor (IF)

1.716

Divison category: 
Organic Chemistry