Rational Drug Design and In vitro Cell Line Studies of Some N-(4-(1Hbenzo[ d]imidazol-2-yl)phenyl)arylamine Derivatives as Aromatase Inhibitors for the Treatment of Cancer

Background: Aromatase is a catalytic enzyme involved in the biosynthesis of estrogen from androgen. It catalyzes the last rate-limiting/crucial critical step in estrogen biosynthesis. Following the success of the aromatase inhibitor, researchers are working on developing a small physiologically active molecule with fewer side effects and improved tolerance. Objectives: Inhibition of the aromatase enzyme, which plays a major role in the rate-limiting phase, is one strategy to prevent estrogen synthesis. After knowing the importance of nitrogen atom containing moieties in the treatment of breast cancer, we have designed some N-(4-(1H-benzo[d]imidazol-2- yl)phenyl)arylamine derivatives through in silico screening such as ADMET analysis and molecular docking studies. From the present investigation, we aimed for the synthesis and biological evaluation of the most potent derivatives obtained in this study. Methods: The selected derivatives were synthesized and confirmed by spectral analysis (FTIR, 1H NMR, and Mass). Cytotoxic activity of the compounds was evaluated by colorimetric MTT assay on MDA-MB-231 (breast adenocarcinoma), MCF-7(breast adenocarcinoma), A549 (lung adenocarcinoma) NCI-H23 (Lung carcinoma) and A-498 (Renal carcinoma) cell line using Doxorubicin hydrochloride as a positive control. Results: From the present investigation, we have concluded that compound 10 [N-(4-(1Hbenzo[ d]imidazol-2-yl)phenyl)-1H-benzo[d]imidazol-5-amine) is most potent and exhibited -9.5 kcal/mol binding affinity. It has formed conventional hydrogen bonds with ALA306 and THR310. It displayed most promising activity with GI50 values 0.796 ± 0.06 μM, 0.695 ± 0.05 μM, 1.14 ± 0.06 μM, 2.15 ± 0.04 μM, and 0.987 ± 0.07 μM against MDAMB-231, MCF-7, A-549, NCI-H23, and A- 498, respectively when compared with Doxorubicin (0.306 ± 0.04 μM, 0.270 ± 0.02 μM, 0.297 ± 0.04 μM, 0.305 ± 0.04 μM, and 0.345 ± 0.09 μM). Conclusion: From the present investigation, it is concluded that the designed molecules had the potential to be developed as broad-spectrum anticancer agents.