QSAR analysis of the anticancer activity of 2,5-disubstituted 9-aza-anthrapyrazoles

The anticancer activity of 35 2,5-disubstituted 9-Aza-Anthrapyrazoles (9-aza-APs) was analyzed employing the Best Multiple Linear Regression (BMLR) as well as a heuristic method for selection of the best descriptors implemented in the CODESSA software to provide a reliable 2D-QSAR model from a set of nearly 500 descriptors. The Chem-X (version 2000) software was used to develop a corresponding 3D-QSAR model. The steric and electrostatic interactions between a probe atom (H') and a set of aligned molecules were assessed using the comparative molecular field analysis method. The results from 2D- and 3D-QSAR analyses show that the anticancer activity of the studied series of 9-aza-APs is strongly dependent on electrostatic interactions. A binding of these derivatives to DNA has been discussed as a key factor determining the cytotoxic activity against tumor cell. The value of the maximum sum partial negative charge at the nitrogen atoms in 9-aza-APs influences strongly the activity of the compounds. The magnitude of these charges define the hydrogen-bond acceptor properties of the 9-aza-APs. The hydrogenbond donor properties of the NH and OH groups in the studied series of compounds also play a key role in the binding process. The stable ring structure of the 9-aza-APs also appears to be an important factor for the antitumor activity of the compounds.