Design, synthesis and biological evaluation of benzo-[ d ]-imidazo-[2,1- b ]-thiazole and imidazo-[2,1- b ]-thiazole carboxamide triazole derivatives as antimycobacterial agents.

Autor: Chitti S; Department of Chemistry, Birla Institute of Technology and Science Pilani, Hyderabad Campus, Jawahar Nagar Hyderabad-500 078 Telangana India kvgc@hyderabad.bits-pilani.ac.in kvgcs.bits@gmail.com +91 40 66303527., Van Calster K; Laboratory of Microbiology, Parasitology and Hygiene, Department of Pharmaceutical Sciences, University of Antwerp Universiteitsplein 1, 2610 Wilrijk Belgium davie.cappoen@uantwerpen.be., Cappoen D; Laboratory of Microbiology, Parasitology and Hygiene, Department of Pharmaceutical Sciences, University of Antwerp Universiteitsplein 1, 2610 Wilrijk Belgium davie.cappoen@uantwerpen.be., Nandikolla A; Department of Chemistry, Birla Institute of Technology and Science Pilani, Hyderabad Campus, Jawahar Nagar Hyderabad-500 078 Telangana India kvgc@hyderabad.bits-pilani.ac.in kvgcs.bits@gmail.com +91 40 66303527., Khetmalis YM; Department of Chemistry, Birla Institute of Technology and Science Pilani, Hyderabad Campus, Jawahar Nagar Hyderabad-500 078 Telangana India kvgc@hyderabad.bits-pilani.ac.in kvgcs.bits@gmail.com +91 40 66303527., Cos P; Laboratory of Microbiology, Parasitology and Hygiene, Department of Pharmaceutical Sciences, University of Antwerp Universiteitsplein 1, 2610 Wilrijk Belgium davie.cappoen@uantwerpen.be., Kumar BK; Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science Pilani Pilani Campus Pilani-333031 Rajasthan India., Murugesan S; Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science Pilani Pilani Campus Pilani-333031 Rajasthan India., Gowri Chandra Sekhar KV; Department of Chemistry, Birla Institute of Technology and Science Pilani, Hyderabad Campus, Jawahar Nagar Hyderabad-500 078 Telangana India kvgc@hyderabad.bits-pilani.ac.in kvgcs.bits@gmail.com +91 40 66303527.
Jazyk: angličtina
Zdroj: RSC advances [RSC Adv] 2022 Aug 10; Vol. 12 (35), pp. 22385-22401. Date of Electronic Publication: 2022 Aug 10 (Print Publication: 2022).
DOI: 10.1039/d2ra03318f
Abstrakt: In the search for new anti-mycobacterial agents, we revealed the importance of imidazo-[2,1- b ]-thiazole and benzo-[ d ]-imidazo-[2,1- b ]-thiazole carboxamide derivatives. We designed, in silico ADMET predicted and synthesized four series of novel imidazo-[2,1- b ]-thiazole and benzo-[ d ]-imidazo-[2,1- b ]-thiazole carboxamide analogues in combination with piperazine and various 1,2,3 triazoles. All the synthesized derivatives were characterized by 1 H NMR, 13 C NMR, HPLC and MS spectral analysis and evaluated for in vitro antitubercular activity. The most active benzo-[ d ]-imidazo-[2,1- b ]-thiazole derivative IT10, carrying a 4-nitro phenyl moiety, displayed IC 90 of 7.05 μM and IC 50 of 2.32 μM against Mycobacterium tuberculosis (Mtb) H37Ra, while no acute cellular toxicity was observed (>128 μM) towards the MRC-5 lung fibroblast cell line. Another benzo-[ d ]-imidazo-[2,1- b ]-thiazole compound, IT06, which possesses a 2,4-dichloro phenyl moiety, also showed significant activity with IC 50 2.03 μM and IC 90 15.22 μM against the tested strain of Mtb. Furthermore, the selected hits showed no activity towards a panel of non-tuberculous mycobacteria (NTM), thus suggesting a selective inhibition of Mtb by the tested imidazo-[2,1- b ]-thiazole derivatives over the selected panel of NTM. Molecular docking and dynamics studies were also carried out for the most active compounds IT06 and IT10 in order to understand the putative binding pattern, as well as stability of the protein-ligand complex, against the selected target Pantothenate synthetase of Mtb.
Competing Interests: Authors declare that there is no conflict of interest.
(This journal is © The Royal Society of Chemistry.)
Databáze: MEDLINE
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