OC-10X

The anti-inflammatory activities of the 2,3-dihydroquinazolin-4(1H)-one derivatives I (R¹ = H; R² = 4-methoxyphenyl, t-Bu, furan-2-yl, etc.; R¹R² = -(CH₂)₆-) and II along with results from our in silico predictions (this study) encouraged us to explore this class of compounds as potential inhibitors of TNF-α (tumor necrosis factor).Among all the mols. assessed in silico the best ranked mols. were identified with the order as I (R¹ = H, R² = 4-chlorophenyl; III); (R¹R² = -(CH₂)₆-; IV); (R¹ = H, R² = pyridin-4-yl; V) based on the estimated total energy.The compound III 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 V and IV.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 III, V and IV 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 III, V and IV 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 pharmacol. interest.

A unique reactivity of 2‐nitrobenzonitrile towards hydrazine hydrate has been demonstrated, which was explored for the rapid and efficient synthesis of dihydro‐quinazolinone derivatives. In this reaction, hydrolysis of nitriles followed by reduction of the nitro group was observed only for the ortho‐isomer. The reaction sequences involve a concerted pathway for the formation of 2‐aminobenzamide from 2‐nitrobenzonitrile, where copper catalyzed both the hydrolysis of the cyano group as well as the reduction of the nitro group simultaneously. This methodology has been used to synthesize a variety of electronically varied spiro‐ and dihydro quinazolinones with high yield and functional group tolerance. In addition, the methodology has also been applied to the synthesis of biologically potent molecular entities.