Sterol 14α-Demethylase Structure-Based Optimization of Drug Candidates for Human Infections with the Protozoan Trypanosomatidae

Sterol
14α-demethylases (CYP51) are cytochrome P450 enzymes
essential for sterol biosynthesis in eukaryotes and therapeutic targets
for antifungal azoles. Multiple attempts to repurpose antifungals
for treatment of human infections with protozoa (Trypanosomatidae)
have been undertaken, yet so far none of them have revealed sufficient
efficacy. VNI and its derivative VFV are two potent experimental inhibitors
of Trypanosomatidae CYP51, effective in vivo against Chagas disease,
visceral leishmaniasis, and sleeping sickness and currently under
consideration as antiprotozoal drug candidates. However, VNI is less
potent against Leishmania and drug-resistant
strains of Trypanosoma cruzi and VFV,
while displaying a broader spectrum of antiprotozoal activity, and
is metabolically less stable. In this work we have designed, synthesized,
and characterized a set of close analogues and identified two new
compounds (7 and 9) that exceed VNI/VFV
in their spectra of antiprotozoal activity, microsomal stability,
and pharmacokinetics (tissue distribution in particular) and, like
VNI/VFV, reveal no acute toxicity.

甾醇14α-去甲基酶（CYP51）是一类真核生物体内参与甾醇生物合成所必需的细胞色素P450酶，同时也是抗真菌唑类药物的治疗靶点。学界已多次尝试将抗真菌药物重新定位，用于治疗原生动物（锥虫科）引发的人类感染，但截至目前均未取得足够疗效。VNI及其衍生物VFV是两款针对锥虫科CYP51的强效实验性抑制剂，在体内可有效对抗恰加斯病、内脏利什曼病与昏睡病，目前已被列为抗原生动物药物候选化合物。然而，VNI对利什曼原虫以及克氏锥虫的耐药菌株活性较弱；而VFV虽具备更广的抗原生动物活性谱，但其代谢稳定性较差。本研究设计、合成并表征了一系列结构紧密的类似物，最终筛选得到两款全新化合物（7号与9号）。相较于VNI/VFV，这两款化合物在抗原生动物活性谱、微粒体稳定性以及药代动力学（尤其是组织分布）方面均更优异，且与VNI/VFV一样，未表现出急性毒性。