Abstract
A series of thirteen new aryl/hetarylbichalcophene-5-carboxamidines was prepared and screened for an in vitro anti-proliferative activity against sixty cancer cell lines. The tested monocationic bichalcophenes displayed promising potent anticancer activity against most cancer cell lines with GI50 values of 1.34–3.09 μM. The most potent compound was derivative 8 (median GI50 and TGI values of 1.34 and 3.23 μM, respectively), being also the least cytotoxic in this bichalcophene series with an LC50 of 77.6 μM. The most responsive cancer cell lines were leukemia (SR and K-562) and colon (HCT-15 and HT29) with GI50 in the sub-micromolar range. The effect of the tested bichalcophenes on normal human lung fibroblast (WI-38) cell line showed that they exerted their antiproliferative activity outside the realms of causing any toxicity in normal cells. To study apoptotic profiles of representatives of this class, compounds 4h, 4i, and 8 were found to cause significant reductions in cdk1 expression in HCT-116 colon cells by 46, 79, and 84%, respectively versus 52% reduction by 5- Flourouracil (5-FU). These three compounds were also unique being the only derivatives that significantly elevated the expression of p53 by ∼2, 4, and 5 folds, respectively. The tested bichalcophenes exhibited moderate to potent antioxidant activity in DPPH and ABTS as well as hydroxyl radical scavenging assays. Moreover, compounds IIIb, IIIc, 4c, and 4i, showed the highest pro-oxidant activity. Finally, to aid future endeavors for optimization of this series, a 5 descriptor 2D-QSAR model was derived from the common physicochemical parameters of these bichalcophenes and the external validation proved the model's good predictive efficiency.
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•A new series of aryl/hetarylbichalcophene-5-carboxamidines was prepared.•The new monoamidines displayed potent anti-proliferative activity.•The most potent and least cytotoxic compound was isoquinoline derivative 8.•The most responsive cancer cell lines were leukemia SR and K-562.•Most of the tested monoamidines exhibited significant selectivity index.