RECEPTOR-BASED DESIGN OF NOVEL DIHYDROFOLATE-REDUCTASE INHIBITORS - BENZIMIDAZOLE AND INDOLE-DERIVATIVES

被引:12
作者
OHEMENG, KA [1 ]
ROTH, B [1 ]
机构
[1] WELLCOME RES LABS,RES TRIANGLE PK,NC 27709
关键词
D O I
10.1021/jm00108a022
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Although many thousands of inhibitors of the enzyme dihydrofolate reductase (DHFR) have been synthesized, all of the very active compounds have been 2,4-diaminopyrimidines or very close analogues. This paper describes 2,4-diamino-6-benzylbenzimidazole (3b) and the corresponding indole (4), as well as more complex tri- and tetracyclic derivatives (5 and 6). These were designed on the basis of molecular modeling to the known X-ray structure of Escherichia coli DHFR, in an effort to determine whether one could drastically alter the diamino configuration by placing one amino substituent in a 5-membered nitrogen-containing ring and the second in the ortho position of a fused ring and still inhibit DHFR significantly. Although the electronics and bond angles are quite different from that of a 2,4-diaminopyrimidine, the pK(a) values are in an appropriate range, and hydrogen-bond distances appear to be quite reasonable. The most active compound, 4, was very unstable and active only in the 10(-4) M range. Dihydroindenoimidazole derivatives such as 6 showed quite a good fit to the enzyme by modeling studies, but had low activity. Since the most active compound made was 2 orders of magnitude weaker as an inhibitor of bacterial DHFR than the unsubstituted 5-benzyl-2,4-diaminopyrimidine, we concluded that such a ring system was unlikely to produce the high inhibitory potency of trimethoprim (1), even with greatly improved hydrophobic contacts. Thus the 2,4-diaminopyrimidine system remains unparalleled to date for the competitive inhibition of this enzyme.
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页码:1383 / 1394
页数:12
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