A series of novel purine linked piperazine derivatives were synthesized to identify new, potent inhibitors of Mycobacterium tuberculosis. The compounds were designed to target MurB disrupting the biosynthesis of the peptidoglycan and exert antiproliferative effects. The first series of purine-2,6-dione linked piperazine derivatives were synthesized using an advanced intermediate 1-(3,4-difluorobenzyl)-7-(but-2-ynyl)-3-methyl-8-(piperazin-1-yl)-1H-purine-2,6(3H,7H)-dione hydrochloride (6) which was coupled with varied carboxylic acid chloride derivatives. Following this piperazine linked derivatives were also synthesized from 6 using diverse isocyanate partners. The anti-mycobacterial activity of the analogues was tested against Mycobacterium tuberculosis H37Rv which revealed a cluster of six analogues (11, 24, 27, 32, 33 and 34), possessed promising activity. In comparison, a set of these new compounds possessed greater potencies relative to current drugs used in the clinic such as Ethambutol. These results were also correlated with computational molecular docking analysis, providing models for strong interactions of the inhibitors with MurB providing a template for the future development of preclinical agents against Mycobacterium tuberculosis.

合成了一系列新颖的嘌呤连接的哌嗪衍生物，以鉴定新的，有效的结核分枝杆菌抑制剂。设计这些化合物以靶向MurB破坏肽聚糖的生物合成并发挥抗增殖作用。使用高级中间体1-（3,4-二氟苄基）-7-（but-2-ynyl）-3-methyl-8-（piperazin-1）合成嘌呤-2,6-二酮连接的哌嗪衍生物的第一系列。 -yl）-1 H-嘌呤-2,6（3 H，7 H）-二酮盐酸盐（6）与各种羧酸氯化物衍生物偶联。此后，哌嗪连接的衍生物也由6使用各种异氰酸酯伙伴。该类似物的抗分枝杆菌活性，对结核分枝杆菌H37Rv显露六个类似物（群集测试11，24，  27，32，33和 34），具有有希望的活性。相比之下，相对于临床上使用的当前药物（如乙胺丁醇），一组这些新化合物具有更大的药效。这些结果还与计算分子对接分析相关，为抑制剂与MurB的强相互作用提供了模型，为抗结核分枝杆菌的临床前药物的未来发展提供了模板。