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In this study, a new series of quinazoline derivatives (- was synthesized and characterized via physicochemical and spectral means. Treatment of 2-amino-5-methylbenzoic acid with butyl isothiocyanate resulted in the new 2-thioxoquinazolin-4-one (. Alkylation and hydrazinolysis of the inherent thioxo group in (-) afforded the corresponding thioethers (-) and hydrazine derivatives ( and ), then was further transformed into tricyclic derivative via cyclocondensation reaction. Compounds and which were previously synthesized, were found to exhibit anticancer activity. The cytotoxicity of all compounds was evaluated against the HeLa and MDA-MB231 cancer cell lines, including and for comparison, using MTT assay. The treatment of the cells was performed with the synthesized compounds and gefitinib at 0, 1, 5, 10, 25, and 50 μM and incubated for 24 h in 50% DMSO. The IC values of the target compounds were reported in μM, using gefitinib as a standard. Our results indicated that all compounds exhibited significant cytotoxicity against both cell lines. While compounds- showed good activity, compounds - were found to be more potent than gefitinib. Thus, compounds - may be potential anticancer agents, with IC values ranging from 1.85 to 2.81 μM in relation to gefitinib (IC = 4.3 and 28.3 μM against HeLa and MDA-MB231 cells, respectively).

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Treatment of patients with triple-negative breast cancer (TNBC) is challenging due to the absence of well- defined molecular targets and the heterogeneity of such disease. In our endeavor to develop potent isatin-based anti-proliferative agents, we utilized the hybrid-pharmacophore approach to synthesize three series of novel isatin-based hybrids 5a–h, 10a–h and 13a–c, with the prime goal of developing potent anti-proliferative agents toward TNBC MDA-MB-231 cell line. In particular, compounds 5e and 10g were the most active hybrids against MDA-MB-231 cells (IC50 = 12.35 ± 0.12 and 12.00 ± 0.13 μM), with 2.37- and 2.44-fold increased activity than 5-fluorouracil (5-FU) (IC50 = 29.38 ± 1.24 μM). Compounds 5e and 10g induced the intrinsic apoptotic mitochondrial pathway in MDA-MB-231; evidenced by the reduced expression of the anti-apoptotic protein Bcl-2, the enhanced expression of the pro-apoptotic protein Bax and the up-regulated active caspase-9 and caspase-3 levels. Furthermore, 10g showed significant increase in the percent of annexin V-FITC positive apoptotic cells from 3.88 to 31.21% (8.4 folds compared to control).