Synthesis of novel thiazole-based 8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepines as potential antitumor and antifungal agents

摘要

A new series of novel thiazole-based 8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepines 6a-g and 7a-g were obtained with high regioselectivity from the reaction of triamino- or tetraaminopyrimidines 4 and 5 with alpha,beta-unsaturated carbonyl compounds 3a-g based on 2,4-dichlorothiazol-5-carbaldehyde 1. Twelve of the synthesized compounds were selected and tested by US National Cancer Institute (NCI) for their antitumor activity against 60 different human tumor cell lines. Compounds 7d and 7g showed important GI(50) ranges of 1.28-2.98 mu M and 035-2.78 mu M respectively under in vitro assays. In addition, 6a-g and 7a-g were tested for antifungal properties against the clinical important fungi Candida albicans and Cryptococcus neoformans. Although these compounds showed moderate activities against Candida albicans, the 2-amino derivatives 7a-g and mainly 7a and 7b, showed high activity against standardized and clinical isolates of Cryptococcus neoformans with MIC50 7.8-31.2 mu g/mL, MIC80 = 15.6-31.2 mu g/mL and MIC100 = 15.6-62.5 mu g/mL. In addition, since both compounds were fungicide rather than fungistatic these thiazole-based 8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepines appear as good candidates for further development not only as antifungal but also as antitumor drugs. (C) 2015 Elsevier Masson SAS. All rights reserved.