Promising anticancer activity with high selectivity of DNA/plasma protein targeting new phthalazin-1(2H)-one heterocyclic scaffolds

There is a crucial requisite to develop new anticancer agents with significant activity to combat cancer which has infected millions worldwide causing an enormous number of deaths. Therefore, in this context, new phthalazin-1(2H)-one nucleus containing heterocyclic scaffolds, 2-(4-chloro-1-oxophthalazin-2(1H)-yl)-N-((1s,4s)-4-hydroxycyclohexyl) acetamide (Z-OP) and 2-(4-chloro-1-oxophthalazin-2(1H)-yl)-N-((1r,4r)-4-hydroxycyclohexyl)acetamide (E-OP), with potent anticancer activities were formulated and characterized here. Results showed that E-OP exhibited promising DNA and plasma protein targeting efficacy greater than that of Z-OP, due to its highly symmetrical structural arrangement. Based on these inspirational results acquired from DNA/plasma protein binding studies, Z-OP and E-OP were systematically investigated for their anticancer activity against human lung carcinoma (A549) and T-cell leukemia (jurkat) cells using MTT assays. Importantly, Z-OP (IC₅₀ = 4.3 µg/mL) and E-OP (IC₅₀= 17 µg/mL) revealed efficient cytotoxicity properties toward the jurkat (IC₅₀ = 4.3 µg/mL for Z-OP; 4.3 µg/mL for E-OP) and A549 cells (IC₅₀ = 31 µg/mL for Z-OP; 17 µg/mL for E-OP), relative to their parent compound L4. Further, Z-OP and E-OP exhibited selective cytotoxicity and safety profiles, as validated using normal human lung (IMR-90) cells (IC₅₀>100 µg/mL for both Z-OP and E-OP). As a part of this study, the drug-likeness, absorption, distribution, metabolism, and excretion (ADME) attributes, as well as in silico toxicity risk assessment for Z-OP and E-OP were established. The results from this study provide a new direction for the development of bioactive heterocyclic scaffolds for future clinical trials to once and for all fully succeed in cancer treatment.