Synthesis and structural elucidation of novel synthetic coumarin scaffolds for their potential pharmacological properties

Abstract

Two novel series of Schiff bases of 3-(2-aminothiazol-4-yl)-6,8-dichloro-2H-chromen-2- one (SVM 1-11) and 3-(2-aminothiazol-4-yl)-6-nitro-2H-chromen-2-one (SVN 1-11) were synthesized and confirmed by FT-IR, NMR, LC-MS and elemental analysis. The resulting compounds were evaluated for anti-tuberculosis activity using the micro Alamar blue assay (MABA) against susceptible strain H37Rv (ATCC25177) and multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB). A computational method was also used to identify the molecular targets for these compounds. Larvicidal and insecticidal activity were evaluated against Anopheles arabiensis using the standard WHO larvicidal assay and cone bioassay methods. Anticancer activity was assessed using the MTT assay against human breast adenocarcinoma cells (MCF-7) and human epithelial lung adenocarcinoma cells (A549). The antioxidant and lipoxygenase inhibitory capacity was measured using the DPPH assay and Lipoxygenase inhibitory kit, respectively. The antimycobacterial efficacy of the synthesized SVM 1-11 showed that SVM 8 and SVM 10 were the most active compounds, with MIC values of 0.5 µg/mL against H37RvMTB and 8 µg/mL against MDR-MTB. Among the synthesized SVN 1-11, the most active compounds were SVN 3 and SVN 4, having MICs of 0.5 and 1 µg/mL against H37Rv-MTB, respectively, and 8 and 4 µg/mL against MDR-MTB. The docking study performed with the target enzymes DprE1and Pks13 indicated that the compounds had a high affinity for the druggable targets DprE1 and Pks13 enzymes of Mycobacterium tuberculosis compared to the reference standards rifampicin and isoniazid. The larvicidal and adulticidal tests revealed that compounds SVM 6 and SVM 9 were the most effective, with larvicidal mortality (100%) equal to the reference drug' Themephos; additionally, the above compounds exhibited significant adulticidal activity of 73.5±1.5 and 77.3±2.3%, respectively. Compounds SVN 6, 7, 8, and 9, on the other hand, were the most potent larvicidal and adulticidal, exhibiting 100% larvae mortality after 24 hours, and significant adulticidal activity. The anticancer activity study indicates that these compounds had a significant effect on MCF-7 cells. SVM 2, 4, 8 and 11 were the most effective with IC50 values ranging from 5.7 to 9.2 µg/mL. Compounds SVN 1, 2, 4, 9, 10, and 11, on the other hand, had a remarkable cytotoxicity effect on MCF-7, with IC50 range from 6.2-16.38 µg/mL. The caspase-Glo® kit test (Caspase 3/7, 8 and 9) was used to assess the mechanism involved in the anticancer activity of the selected active compounds against MCF-7. The results showed that the apoptosis generated by these compounds was triggered in part by the activation of caspase-3/7 and caspase-9, which may be the primary mechanism of apoptosis. The antioxidant results revealed that compounds SVM 3 and SVM 8 were the most potent, with a percentage scavenging capacity of 92.7±1.1 and 89.7±1.7%, respectively. Compounds SVN 5 and 9, on the other hand, were the most active, with a percentage scavenging capacity of 80.5±0.6 and 85.4±1.3%, respectively. The lipoxygenase inhibitory assay revealed that compounds SVM 3, 8, and 11 were the most potent LO inhibitors, with inhibitory capacity ranging from 60 to 67%. Compound SVN 11, on the other hand, was the most effective, with a percentage inhibitory capacity of 61.3±0.3%. Our results suggest that integrating different functional groups on the phenyl ring at the fourth position of the thiazole moiety, connected to the primary coumarin nucleus at the third position, contributed significantly to the biological activity of the compounds. These active compounds could be used as a scaffold for structural optimization to develop highly effective and selective antimycobacterial, anticancer, antioxidant, larvicidal, and adulticidal agents and promote further development of more efficient lipoxygenase inhibitors of novel structurally similar analogues.