Abstract
[Display omitted]
•New thiophene, thienopyridine, and thiazoline-based derivatives 5a-c, 7, 9, 12a,b, and 14a,b were designed and synthesized.•The cytotoxic activity of the new compounds was evaluated in vitro against the liver (HepG-2), breast (MCF-7), colon (HCT-116), and WI-38 cell lines.•The most promising cytotoxic agents 5a-c were examined as multitargeting inhibitors against Pim, VEGFR, and EGFRWT.•The impact of compound 5c was evaluated on the cell cycle, apoptosis, and the proapoptotic parameters Bax/Bcl-2 ratio, p53, and caspase-3.•Antimicrobial assay of all compounds was carried against different types of pathogenic gram-positive, gram-negative bacteria and fungi.•Molecular docking results of compounds 5a proved its promising binding interactions with Pim, VEGFR, and EGFRWT. In silico ADMET studies were carried out to explore the drug-likeness properties of the new compounds.
Multitargeting kinase inhibitors recently proved to be a profitable approach for conquering cancer proliferation. The current study represents the design and synthesis of new thiophene, thienopyridine, and thiazoline-based derivatives 4-14a,b. All the target compounds were examined in vitro against three cancer cell lines; the liver (HepG-2), breast (MCF-7), and colon (HCT-116) where the thiophene-based compounds 5a-c, demonstrated the most potent activity. Furthermore, the latter derivatives revealed a safety profile against WI-38 normal cell line of selectivity indices ranging from 4.43 to 17.44. In vitro enzyme assay of 5a-c revealed that the carbohydrazide analog 5c has the most promising multitargeting inhibiting activity against Pim-1, VEGFR-2, and EGFRWT enzymes of IC50 values; 0.037 ± 0.02, 0.95 ± 0.24, and 0.16 ± 0.05 µM, respectively. As it was the most potent analog, 5c was further subjected to cell cycle and apoptosis analysis. The results indicated that it induced preG1 arrest and an apoptotic effect in the early and late stages. Moreover, further apoptosis studies were carried out for 5c to evaluate its proapoptotic potential. Interestingly, 5c enhanced the levels of Bax/Bcl-2 ratio, p53, and active caspase 3 by 18, 6.4, and 24 folds, respectively compared to the untreated cells. The antimicrobial evaluation showed that only compounds 3 and 5a produced broad-spectrum potency, while 5b and 5c exhibited outstanding antifungal effects. Finally, a molecular docking study was carried out to discover the probable interactions of compound 5c with the active sites of Pim-1, VEGFR-2, and EGFRWT kinases.