β-carboline consists of a pyridine ring fused to an indole skeleton; it possesses numerous pharmacological activities, including anticancer. Previously, we reported a satisfactory 2D and 3D QSAR study on β-carboline derivatives. Based on QSAR studies, we designed, synthesized, characterized, and screened fourteen β-carboline derivatives for anticancer activity. Eleven of them demonstrated potent anticancer activity against both liver (HepG2) and adenocarcinoma (A549) cell lines. Compound 1-(N, N-dimethylbenzenamine)-3-(4-(p-tolylmethanimine)-5-thio-1, 2, 4-triazol-3-yl) β-carboline (9) was found to be most potent against both cancer cell lines and equipotent towards standard drug Adriamycin. Compounds 1-(p-tolyl)-3-(4-(p-(iminomethyl)-N, N-dimethylbenzenamine) -5-thio-1, 2, 4-triazol-3-yl) β-carboline (4) and 1-(N, N-dimethylbenzenamine)-3-(4-(m-tolylmethanimine)-5-thio-1, 2, 4-triazol-3-yl) β-carboline (10) were found to be 7 to 10 times less potent as compared to Adriamycin against the HepG2 cell line. Molecular docking was also performed with the Glide docking program to explore the binding mode between the synthesized β-carboline derivatives and the receptor CDK2 [1AQ1] protein.

Quantitative structure–activity relationship studies have been performed on twenty one β-carboline derivatives to investigate the structural requirements for antitumor activity. The best 2D-QSAR model (r2 = 0.802, F = 24.321, r2se = 0.325) indicated statistical significance and internal predictivity of the developed model shown by the value of cross validated squared correlation coefficient which was 0.724. A five-point pharmacophore hypothesis yielded ligand based pharmacophore 3D-QSAR models with good partial least-square (PLS) statistics results. The training set and test set correlation was characterized by PLS factors (r 2 = 0.842, SD = 0.306, F = 21.3, P = 4.27e -05, Q2 ext = 0.748, RMSE = 0.531, Pearson-R = 0.975). A docking study revealed the binding orientations of DNA intercalates at active site of amino acid residues. The results of 2D-QSAR and 3D-QSAR give detailed structural insights and at the same time highlight the important binding features of novel β-carboline derivatives as antitumor agents.

β-Carboline moieties are important structural subunits which occur as components of many biologically interesting molecules for antitumor activity. Quantitative structure–activity relationship (QSAR) studies have been performed on β-carboline derivatives to explore the structural necessities for antitumor activity. 3D QSAR studies were done using V-Life Sciences MDS 3.0 drug designing module to explain the structural requirements for the anti-tumor activity. The 3D-QSAR was performed using the Step Wise K Nearest Neighbour Molecular Field Analysis [(SW) kNN MFA] technique with the partial least-square (PLS) method on a database. Obtained best 3D-QSAR model having high predictive ability with q2=0.743, r2=0.721, pred_r2=0.708 and standard error=0.346, explaining the majority of the variance in the data with partial least square (PLS) components. The results of the present study may be useful on the designing of more potent compounds as antitumor drugs