C-2苯环上取代基对喹唑啉-4-酮烷基化的影响及化合物抗肿瘤、抗菌活性

Effects of the Substituent at C-2 Phenyl on the N-/O-Alkylation of Quinazolin-4(3H)-one and Anti-Tumor, Antimicrobial Activities of Some Compounds

邻氨基苯甲酰胺与取代苯甲醛反应,合成了含氨烷基侧链的喹唑啉-4-酮4和5,探讨了C-2位苯环取代基对喹唑啉-4-酮内酰胺N-/O-烷基化的影响,并评价了部分化合物的抗肿瘤细胞增殖活性及抑菌活性.结果表明,当C-2苯环上的取代基在邻位时,N-烷基化反应为主;而在间位或对位时,以O-烷基化为主,立体效应起到了主导作用.4-{2-{{2-[3-(苄氧基)苯基]喹唑啉-4-基}氧基}乙基}吗啉(4h)具有较好的抗肺癌细胞增殖活性,IC_(50)值为13.20μmol/L.2-(2-氯苯基)-3-[2-(哌啶-1-基)乙基]喹唑啉-4(3H)-酮(5aa)和2-[3-(苄氧基)苯基]-4-[2-(吡咯啉-1-基)乙氧基]喹唑啉(4hb)(50μg/m L)对大肠杆菌和痢疾杆菌具有显著的抑制活性,抑菌率分别为100%,100%和100%,96%.化合物5aa对链铬孢菌真菌的抑制率为100%.

A series of quinazolin-4（3H）-one derivatives 4 and 5 possessing amino alkyl side chain were synthesized by the condensation reaction of 2-aminobenzamide with substituted benzaldehyde, followed by SN2 substitution reaction with haloalkane. The effects of the substituent at C-2 phenyl on the N-/O-alkylated reaction of quinazolin-4（3H）-one were explored. Some compounds were also evaluated for their anti proliferation activities and antimicrobial activities. The results showed that when the substituent was at orth O-position on C-2 phenyl, N-alkylation was the main reaction, while at meta- or para-positions, O-alkylation was predominant, which suggested that the steric factor played a key role on this ambident nuclophilic substitution. 4-（2-（（2-（3-（Benzyloxy）phenyl）quinazolin-4-yl）oxy）ethyl）morpholine （4h） showed relatively good anti-proliferative activity against A549 tumor cells with the IC50 value of 13.20 μmol/L. 2-（2-Chlorophenyl）-3-（2-（piperidin-1-yl）ethyl）quinazolin-4（3H）-one （5aa） and 2-（3-（benzyloxy）phenyl）-4-（2-（pyrrolidin-1-yl）ethoxy）quinazoline （4hb） exhibited significant anti Esche-richia coli or Shigella castellani activities, and the inhibition rates were near 100% at the concentration of 50 μg/mL. The inhi-bition rate of compound 5aa against Alternaria alternate was 100%.