Novel Quinoline-Based Bis -Oxadiazole Derivatives as Potent Anticancer Targets: Efficient Synthesis, Molecular Modeling, and ADME-T Studies

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The search for novel potent anticancer agents is considered a rapidly advancing field and viewed as a constantly evolving area within medicinal chemistry. Twelve new compounds with quinoline side chains connected to bis-oxadiazoles and terminal lipophilic aryl portions with substantial substituent functions were created and synthesized using the EDC coupling reaction in an effort to find new treatments for the cancer epidemic. These compounds were structurally deduced using modern spectroscopic techniques (1H-,13C–NMR, and HRMS). Based on the EGFRWT inhibitory effects, compounds 7c and 7 l exhibited the most potent inhibitory activity with IC50 values of1.75 ± 1.10 μM and 1.60 ± 0.25 μM, when compared to Erlotinib (IC50 = 2.04 ± 0.78 μM). Additionally, it demonstrated notable activity against HT-29 cells, with an IC50 value of 6.65 ± 0.47 μM. In contrast, compound 7 l showed the highest selectivity for MCF-7 inhibition (IC50 = 5.67 ± 2.70 μM), outperforming the reference drug doxorubicin, which displayed an IC50 value of 6.44 ± 1.39 μM. Compound 7f inhibited cell viability by 97.42%, indicating it is the least cytotoxic compared to 7a and 7 l on the normal NCM460 cell line. The binding interactions of the best inhibitory ligands within the active region of breast cancer in EGFR were further verified by molecular docking predictions, which highlighted the significant hydrophobic and hydrogen-bonding interactions (PDB code: 1M17). The drug-like characteristics of these chemical structures (7a–7l) were confirmed by pharmacokinetic investigation of the newly synthesized oxadiazoles, which revealed positive qualities with regard to absorption, distribution, metabolism, excretion, and toxicity (ADME–T). As a result, it is strongly advised that these agents be studied further in clinical trials.

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