FNDR-20081 [4-{4-[5-(4-Isopropyl-phenyl)- [1,2,4]oxadiazol-3-ylmethyl]-piperazin-1-yl}-7-pyridin-3-yl-quinoline] is a novel, first in class anti-tubercular pre-clinical candidate against sensitive and drug-resistant Mycobacterium tuberculosis (Mtb). In-vitro combination studies of FNDR-20081 with first- and second-line drugs exhibited no antagonism, suggesting its compatibility for developing new combination-regimens. FNDR-20081, which is non-toxic with no CYP3A4 liability, demonstrated exposure-dependent killing of replicating-Mtb, as well as the non-replicating-Mtb, and efficacy in a mouse model of infection. Whole genome sequencing (WGS) of FNDR-20081 resistant mutants revealed the identification of pleotropic targets: marR (Rv0678), a regulator of MmpL5, a transporter/efflux pump mechanism for drug resistance; and Rv3683, a putative metalloprotease potentially involved in peptidoglycan biosynthesis. In summary, FNDR-20081 is a promising first in class compound with the potential to form a new combination regimen for MDR-TB treatment.

FNDR-20081 [4-{4-[5-(4-异丙基-苯基)-[1,2,4]恶二唑-3-基甲基]-哌嗪-1-基}-7-吡啶-3-基-喹啉] 是一种新型的、一流的抗结核病临床前候选药物，可对抗敏感和耐药结核分枝杆菌(Mtb)。FNDR-20081 与一线和二线药物的体外联合研究没有显示出拮抗作用，表明它与开发新的联合方案具有相容性。FNDR-20081 无毒且无 CYP3A4 责任，在小鼠感染模型中表现出暴露依赖性杀死复制型 Mtb 以及非复制型 Mtb 和功效。FNDR-20081 抗性突变体的全基因组测序 (WGS) 揭示了多效性靶标的鉴定：marR(Rv0678)，一种 MmpL5 的调节剂，一种用于耐药性的转运蛋白/外排泵机制；和 Rv3683，一种推定的金属蛋白酶，可能参与肽聚糖的生物合成。总之，FNDR-20081 是一种很有前途的一流化合物，有可能形成一种新的耐多药结核病联合治疗方案。