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A series of benzo[b]thiophene and their benzo[4,5]thieno[3,2-b]pyran derivatives (3a-f), (4a-f), (5a-f) and 6 were synthesized and characterized by spectroscopic and elemental analysis. All compounds were subjected to one dose anticancer screening in NCI- America, but only the compounds gave high percent growth inhibition were further subjected to five dose screening. A good result of compound 4f with GI50 = 0.15 µmol, TGI= 1.14 µmol and 4c with GI50 = 1.09 µmol, TGI = 10.19 µmol, LC50 = 100 µmol on HT-29 cell line. To explore mechanism of cytotoxicity, compound 4f and 4c were allowed to affect cell cycle progression using HT-29 cell line (human colon cancer) in two-time interval (24 and 48 hr). The cytotoxicity of 4f and 4c was correlated with induction of apoptosis causing pre-G1apoptosis and cell growth arrest at G2/M in a time dependant manner through inhibition of CDK-2. For exploring the SAR for all synthesized compounds, IC50 of 5d was determined which was equal to 0.32 ±0.05 µmol, IC50 of 6 was equal to be 0.15 ±0.01 µmol while IC50 of erlotinib reference was equal to 0.3±0.02 µmol. Finally we were able to synthesize a series of benzo[b] thiophene, benzo[4,5]thieno[3,2-b]pyran having a good cytotoxic activity suggesting promising anticancer derivatives.

New cytotoxic agents based on benzothienopyrimidine scaffold were designed, synthesized, and evaluated against the MCF‐7 breast cancer line in comparison to erlotinib and letrozole as reference drugs. Eight compounds demonstrated up to 20‐fold higher anticancer activity than erlotinib, and five of these compounds were up to 11‐fold more potent than letrozole in MTT assay. The most promising compounds were evaluated for their inhibitory activity against EGFR and ARO enzymes. Compound 12, which demonstrated potent dual EGFR and ARO inhibitory activity with IC50 of 0.045 and 0.146 µM, respectively, was further evaluated for caspase‐9 activation, cell cycle analysis, and apoptosis. The results revealed that the tested compound 12 remarkably induced caspase‐9 activation (IC50 = 16.29 ng/ml) caused cell cycle arrest at the pre‐G1/G1 phase and significantly increased the concentration of cells at both early and late stage of apoptosis. In addition, it showed a higher safety profile on normal MCF‐10A cells, and higher antiproliferative activity on cancer cells (IC50 = 8.15 µM) in comparison to normal cells (IC50 = 41.20 µM). It also revealed a fivefold higher selectivity index than erlotinib towards MCF‐7 cancer cells. Docking studies were performed to rationalize the dual inhibitory activity of compound 12.

A series of [1]benzothieno[2,3- c ]pyridines was synthesised. Most compounds were chosen by NCI-USA to evaluate their anticancer activity. Compounds 5a–c showed prominent growth inhibition against most cell lines. 5c was selected at five dose concentration levels. It exhibited potent broad-spectrum anticancer activity with a GI 50 of 4 nM–37 µM. Cytotoxicity of 5a–c was further evaluated against prostate, renal, and breast cancer cell lines. 5c showed double and quadruple the activity of staurosporine and abiraterone, respectively, against the PC-3 cell line with IC 50 2.08 µM. The possible mechanism of anti-prostate cancer was explored via measuring the CYP17 enzyme activity in mice prostate cancer models compared to abiraterone. The results revealed that 5c suppressed the CYP17 enzyme to 15.80 nM. Moreover, it was found to be equipotent to abiraterone in testosterone production. Cell cycle analysis and apoptosis were performed. Additionally, the ADME profile of compound 5c demonstrated both good oral bioavailability and metabolic stability.

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New thiazolopyrimidine derivatives 2, 3a-d, 4a-c, 5, 6a-c, and 7a,b were synthesised. All prepared compounds were evaluated by MTT cytotoxicity assay against three human tumour cell lines. Compounds 3c, 3d, 4c, 6a, 6b, and 7b exhibited potent to strong anticancer activity that was nearly comparable or superior to Doxorubicin. Compounds exhibiting significant cytotoxicity were further selected to study their inhibitory activity on the Topo II enzyme. Compound 4c was the most potent Topo II inhibitor with an IC 50 value of 0.23 ± 0.01 µM, which was 1.4-fold and 3.6-fold higher than the IC 50 values of Etoposide and Doxorubicin. Furthermore, compound 4c showed significant cell cycle disruption and apoptosis on A549 cells compared to control cells. Molecular docking of the most active compounds illustrated proper fitting to the Topo II active site, suggesting that our designed compounds are promising candidates for the development of effective anticancer agents acting through Topo II inhibition.

Following the pharmacophoric features of vascular endothelial growth factor receptor 2 (VEGFR‐2) inhibitors, a novel thieno[2,3‐d]pyrimidine derivative has been designed and its activity against VEGFR‐2 has been demonstrated by molecular docking studies that showed an accurate binding mode and an excellent binding energy. Furthermore, the recorded binding was confirmed by a series of molecular dynamics simulation studies, which also revealed precise energetic, conformational, and dynamic changes. Additionally, molecular mechanics with generalized Born and surface area solvation and polymer‐induced liquid precursors studies were conducted and verified the results of the MD simulations. Next, in silico absorption, distribution, metabolism, excretion, and toxicity studies have also been conducted to examine the general drug‐like nature of the designed candidate. According to the previous results, the thieno[2,3‐d]pyrimidine derivative was synthesized. Fascinatingly, it inhibited VEGFR‐2 (IC50 = 68.13 nM) and demonstrated strong inhibitory activity toward human liver (HepG2), and prostate (PC3) cell lines with IC50 values of 6.60 and 11.25 µM, respectively. As well, it was safe and showed a high selectivity index against normal cell lines (WI‐38). Finally, the thieno[2,3‐d]pyrimidine derivative arrested the growth of the HepG2 cells at the G2/M phase inducing both early and late apoptosis. These results were further confirmed through the ability of the thieno[2,3‐d]pyrimidine derivative to induce significant changes in the apoptotic genes levels of caspase‐3, caspase‐9, Bcl‐2 associated X‐protein, and B‐cell lymphoma 2.

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