Moodley Rashmika, Mashaba Chakes, Rakodi Goitsemodimo H, Ncube Nomagugu B, Maphoru Mabuatsela V, Balogun Mohammed O, Jordan Audrey, Warner Digby F, Khan Rene, Tukulula Matshawandile
School of Chemistry and Physics, University of KwaZulu Natal, Westville Campus, Durban 4000, South Africa.
Department of Chemistry, Tshwane University Technology, Pretoria 0001, South Africa.
Pharmaceuticals (Basel). 2022 May 5;15(5):576. doi: 10.3390/ph15050576.
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.
通过包含酰胺化偶联反应这一关键步骤的三步合成序列，成功合成了一系列25种新型苯并噻唑-脲-喹啉杂化化合物。通过常规光谱工具（1H和13C NMR以及IR）和质谱（HRMS）对合成化合物的结构进行了确认。对这些杂化化合物针对结核分枝杆菌H37Rv pMSp12::GPF生物报告菌株的抗结核抑制活性进行了体外评估。在25种测试化合物中，17种表现出有前景的抗结核活性，MIC90小于62.5 μM。具体而言，13种化合物（6b、6g、6i - j、6l、6o - p、6r - t和6x - y）表现出有前景的活性，MIC90值在1 - 10 μM范围内，而化合物6u活性最高，在CAS测定中表现出亚微摩尔活性（0.968 μM）。此外，在17种化合物中的11种各自的MIC90浓度下，观察到对HepG2细胞系的细胞毒性极小（细胞活力高于75%），6u表现出100%的细胞活力。喹啉、脲和苯并噻唑支架的杂化显示出协同关系，因为所得杂化物的活性与单个实体相比有了极大提高。计算机辅助ADME预测表明，这些化合物中的大多数具有类药物性质，不太可能潜在地引起心脏毒性（QPlogHERG > -5）。本研究获得的结果表明，大多数合成化合物可作为未来作为新型抗分枝杆菌药物进行优化的有价值起点。
