Anti-proliferative and ADMET screening of novel 3-(1H-indol-3-yl)-1, 3-diphenylpropan-1-one derivatives

Manjunatha K Siddappa,Manjulatha K,Nayak D Satyanarayan,Kaviraj M Yarbagi,Adarsha H Jagadeesha

doi:10.1080/23312009.2016.1172542

Abstract

AbstractCancer tends to be one of the major diseases in the present century affecting global population, and proliferation of cancerous cells needs to be eliminated as the cell growth is uncontrolled. In this present study, a series of facile, high yielding 3-(1H-indol-3-yl)-1, 3-diphenylpropan-1-ones 3(a–j) was designed, synthesized and evaluated for anti-proliferative activity against different human cancer cell lines; MCF-7 (breast cancer), K562 (leukemic cancer), HeLa (cervical cancer), Colo205 (colorectal adreno carcinoma), HepG2 (Hepato cellular carcinoma) cell lines. The compounds 3a, 3c, 3d, 3e, 3f, 3g and 3j exhibited an average inhibition of 35% against Hepatocellular Carcinoma (Hepg2) cell lines whereas, compounds 3a, 3c, 3d and 3e exhibited 33, 31, 35 and 33% inhibition, respectively, against HeLa cells at 10 μm concentrations. Doxorubicin was employed as a positive control. The ADME-TOX data was obtained by subjecting the molecules in silico to quantitatively predict the physicochemical prope...

Highlights

The results indicated that the tested molecules were active against HeLa and Hepg2 cancer cell lines and further help us to identify possible lead moieties as anti-proliferative agent(s)
Procedure for the synthesis of 3-(1H-indol-3-yl)-1, 3-diphenylpropan-1-one (3a) To the stirred solution of chalcone (0.25 g, 1 m mol), indole (0.12 g, 1 m mol) in ethanol (5 ml), concentrated HCl 5 m mol% was added and the reaction mixture was kept for reflux on water bath until the completion of reaction indicated by TLC
The method was standardized to achieve complete conversion of the reaction with 5 mmol% of hydrochloric acid in ethanol which was sufficient in the synthesis of 3-(1H-indol-3-yl)-1, 3 diphenylpropan-1-ones with excellent yields (Table 1)

Summary

Introduction

Indole nucleus has been the central dogma for many natural as well as synthetic pharmaceutical potent molecules (Abdel-Rahman, 2010; Kameshwara et al, 2011) and are known to exhibit many pharmacological activities such as, anticancer (Chen, Safe, & Bjeldanes, 1996; Ekhlass, 2010; Vishal et al, 2012), antioxidant (Suzen & Buyukbingol, 2000), antirhemuatoidal, anti-HIV (Buyukbingol, Suzen, & Klopman, 1994; Suzen & Buyukbingol, 1998) and has the ability to selectively inhibit farnesyl transferase (Rodney & Fernandes, 2008). In view of the above studies, the present study prompted us to take indole as moiety and design the structure around with a rationality to be used as potential leads for cancer therapy, because of its ability to interact and inhibit with various enzymes involved in cancer It has kept our interest in synthesizing 3-(1H-indol-3-yl)-1, 3-diphenylpropan-1-ones 3(a–j) derivatives (Arrigo, Rosaria, & Maria, 2009; Jianwei et al, 2010; Xiang, Haibo, & Yu, 2011; Zhi-Liang, Shun-Jun, & Teck-Peng, 2008) by condensing indole with different chalcones, thereby increasing the characteristic properties of the molecules to obtain a better moiety for the treatment of cancer. The addition of indole to α,β-unsaturated ketones was achieved (Marco et al, 2002) by using HCl as catalyst in the synthesis of title compounds with excellent yields because of its efficient conversion and can overcome the drawbacks such as low yield, prolong reaction time, solubility of the catalyst in solvents and isolation of the product in good yield without hindrance because of its water solubility

Experimental

Spectral data

Results and discussion

Evaluation of anti-proliferative activity

SAR data interpretation

Conclusion