Synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives as potential inhibitors of TNF-α

Abstract

'The anti-inflammatory activities of the 2,3-dihydroquinazolin-4(1H)-one derivatives along with results from our in silico predictions (this study) encouraged us to explore this class of compounds as potential inhibitors of TNF-α. Among all the molecules assessed in silico the best ranked molecules were identified with the order as 3h > 3p > 3l based on the estimated total energy. The compound 3h participated in a H-bond interaction through its C = O group of the quinazoline-4(1H)-one ring with TYR151 of chain A in addition to the interactions with all the critical TYR residues via its chloro group. The interesting docking results were also obtained for compound 3l and 3p. For the access of this class of fused N-heteroarenes we adopted the β-cyclodextrin (β-CD) catalyzed approach involving the cyclocondensation of 2-aminobenzamide with aldehydes / ketones in pure water. Various aromatic, aliphatic and heteroaromatic aldehydes (including the cinnamaldehyde) along with ketones were employed for this purpose to afford the corresponding product in good to excellent yield. The recovery and recycling of the catalyst β-CD was successful. The inexpensive and eco-friendly nature along with the simple product purification as well as good product yield are the key advantages of this approach. When examined in vitro the compound 3h, 3l and 3p with the inhibition > 70% emerged as the most active compounds in this series as predicted by in silico studies. According to the SAR (Structure Activity Relationship) the effectiveness of the C-2 aryl group was found to be in the order Ar = C6H4Cl-p > 4-pyridyl > C6H4OMe-p > C6H2(OMe)3-m,p > C6H4OH-p etc. whereas an heteroaryl or alkyl group at this position was found to be less effective or ineffective. In terms of IC50 values the compound 3h, 3l and 3p appeared as superior than the known inhibitor thalidomide though they were not better than rolipram. Being identified as preliminary hits these compounds are of further pharmacological interest.