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New Quinoline–Urea–Benzothiazole Hybrids as Promising Antitubercular Agents: Synthesis, In Vitro Antitubercular Activity, Cytotoxicity Studies, and In Silico ADME Profiling

Authors :
Rashmika Moodley
Chakes Mashaba
Goitsemodimo Rakodi
Nomagugu Ncube
Mabuatsela Maphoru
Mohammed Balogun
Audrey Jordan
Digby Warner
Rene Khan
Matshawandile Tukulula
Source :
Pharmaceuticals; Volume 15; Issue 5; Pages: 576
Publication Year :
2022
Publisher :
Multidisciplinary Digital Publishing Institute, 2022.

Abstract

A series of 25 new benzothiazole–urea–quinoline hybrid compounds were synthesized successfully via a three-step synthetic sequence involving an amidation coupling reaction as a critical step. The structures of the synthesized compounds were confirmed by routine spectroscopic tools (1H and 13C NMR and IR) and by mass spectrometry (HRMS). In vitro evaluation of these hybrid compounds for their antitubercular inhibitory activity against the Mycobacterium tuberculosis H37Rv pMSp12::GPF bioreporter strain was undertaken. Of the 25 tested compounds, 17 exhibited promising anti-TB activities of less than 62.5 µM (MIC90). Specifically, 13 compounds (6b, 6g, 6i–j, 6l, 6o–p, 6r–t, and 6x–y) showed promising activity with MIC90 values in the range of 1–10 µM, while compound 6u, being the most active, exhibited sub-micromolar activity (0.968 µM) in the CAS assay. In addition, minimal cytotoxicity against the HepG2 cell line (cell viability above 75%) in 11 of the 17 compounds, at their respective MIC90 concentrations, was observed, with 6u exhibiting 100% cell viability. The hybridization of the quinoline, urea, and benzothiazole scaffolds demonstrated a synergistic relationship because the activities of resultant hybrids were vastly improved compared to the individual entities. In silico ADME predictions showed that the majority of these compounds have drug-like properties and are less likely to potentially cause cardiotoxicity (QPlogHERG > −5). The results obtained in this study indicate that the majority of the synthesized compounds could serve as valuable starting points for future optimizations as new antimycobacterial agents.

Details

Language :
English
ISSN :
14248247
Database :
OpenAIRE
Journal :
Pharmaceuticals; Volume 15; Issue 5; Pages: 576
Accession number :
edsair.doi.dedup.....906ab04434c81e4a0def17df2f1772f5
Full Text :
https://doi.org/10.3390/ph15050576