Benzimidazole-based derivatives as privileged scaffold developed for the treatment of the RSV infection: a computational study exploring the potency and cytotoxicity profiles

Abstract

Respiratory syncytial virus (RSV) has been identified as a main cause of hospitalisation in infants and children. To date, the current therapeutic arsenal is limited to ribavirin and palivizumab with variable efficacy. In this work, starting from a number of in-house series of previously described anti-RSV agents based on the benzimidazole scaffold, with the aim at gaining a better understanding of the related chemical features involved in potency and safety profiles, we applied a computational study including two focussed comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The results allowed us to derive useful suggestions for the design of derivatives and also to set up statistical models predicting the potency and selectivity index (SI = CC₅₀/EC₅₀) of any new analogue prior to synthesis. Accordingly, here, we discuss preliminary results obtained through the applied exhaustive QSAR analyses, leading to design and synthesise more effective anti-RSV agents.

Keywords: 3D-QSAR; Benzimidazoles; CoMFA; CoMSIA; respiratory syncytial virus.

Figure 1.

General structures of benzimidazole-based anti-RSV agents

Scheme 1.

Reagents and conditions: (a) 120 °C, 9 h; (b) SnCl₂ . 2H₂O, conc. HCl, EtOH, 6 h at reflux; (c) 180°, N₂, 90 min.

Figure 2.

Contour map of model A CoMFA steric regions are shown around the anti-RSV agent 44 (a) and 11 (b). The compounds are displayed in ball and stick mode.

Figure 3.

Contour map of model A CoMFA steric regions are shown around the anti-RSV agent 126 (a) and 148 (b). The compounds are displayed in ball and stick mode.

Figure 4.

Contour maps of model A CoMFA electrostatic regions are shown around the anti-RSV agents 44 (a) and 11 (b). The compounds are displayed in ball and stick mode.

Figure 5.

Contour maps of model A CoMFA electrostatic regions are shown around the anti-RSV agents 126 (a) and 148 (b). The compounds are displayed in ball and stick mode.

Figure 6.

Model A CoMSIA hydrophobic favoured and disfavoured regions are shown around the anti-RSV agents 126 (a) and 148 (b). The compounds are displayed in ball and stick mode.

Figure 7.

Model A CoMSIA H-bond acceptor favoured and disfavoured contour maps are displayed around benzimidazoles 126 (a) and 148 (b). The compounds are displayed in ball and stick mode.

Figure 8.

Model A CoMSIA H-bond donor favoured and disfavoured contour maps are shown around the anti-RSV agents 126 (a) and 148 (b). The compounds are displayed in ball and stick mode.

Figure 9.

Contour map of model B CoMFA steric regions are shown around the anti-RSV agent 95 (a) and 156 (b). The compounds are displayed in ball and stick mode.

Figure 10.

Contour maps of model B CoMFA electrostatic regions are shown around the anti-RSV agents 95 (a) and 156 (b), represented in stick mode.

Figure 11.

Model B CoMSIA hydrophobic favoured and disfavoured regions are shown around the anti-RSV agents 95 (a) and 156 (b), represented in stick mode.

Figure 12.

Model B CoMSIA H-bond acceptor favoured and disfavoured contour maps are displayed around benzimidazoles 95 (a) and 156 (b), depicted in stick mode.

Figure 13.

Model B CoMSIA H-bond donor favoured and disfavoured contour maps are shown around the anti-RSV agents 95 (a) and 156 (b), represented in stick mode.

Figure 14.

Chemical structure of the anti-RSV agent BMS-433771.

Figure 15.

Chemical structures and biological data about the prototypes 120, 126 and the 5-methyl newly synthesised analogues 157, 158.