OC-10X

A series of novel 2-substituted 2, 3-dihydroquinazolin-4(1H)-one derivatives were designed, synthesized and estimated for their in vitro antiproliferative activities against HepG2, U251, PANC-1, A549 and A375 cell lines. Among them, compound 32 was the most promising candidate, and displayed strong broad-spectrum anticancer activity. The mechanism studies revealed that compound 32 inhibited tubulin polymerization in vitro, disrupted cell microtubule networks, arrested the cell cycle at G2/M phase, and induced apoptosis by up-regulating the expression of cleaved PARP-1 and caspase-3. Furthermore, molecular docking analysis suggested that compound 32 well occupied the binding site of tubulin. In addition, compound 32 exhibited no significant activity against 30 different kinases respectively, indicating considerable selectivity. Moreover, compound 32 significantly inhibited the tumour growth of the HepG2 xenograft in a nude mouse model by oral gavage without apparent toxicity. These results demonstrated that some 2-substituted 2, 3- dihydroquinazolin-4(1H)-one derivatives bearing phenyl, biphenyl, naphthyl or indolyl side chain at C₂-position might be potentially novel antitumor agents as tubulin polymerization inhibitors.

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.