Laboratory of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens15771, Greece.
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois61801, United States.
ACS Infect Dis. 2023 Feb 10;9(2):342-364. doi: 10.1021/acsinfecdis.2c00537. Epub 2023 Jan 27.
SQ109 is a tuberculosis drug candidate that has high potency against and is thought to function at least in part by blocking cell wall biosynthesis by inhibiting the MmpL3 transporter. It also has activity against bacteria and protozoan parasites that lack MmpL3, where it can act as an uncoupler, targeting lipid membranes and Ca homeostasis. Here, we synthesized 18 analogs of SQ109 and tested them against , , , , and , as well as against the protozoan parasites , , , , and . Activity against the mycobacteria was generally less than with SQ109 and was reduced by increasing the size of the alkyl adduct, but two analogs were ∼4-8-fold more active than SQ109 against , including a highly drug-resistant strain harboring an A309P mutation in MmpL3. There was also better activity than found with SQ109 with other bacteria and protozoa. Of particular interest, we found that the adamantyl C-2 ethyl, butyl, phenyl, and benzyl analogs had 4-10× increased activity against asexual blood stages, together with low toxicity to a human HepG2 cell line, making them of interest as new antimalarial drug leads. We also used surface plasmon resonance to investigate the binding of inhibitors to MmpL3 and differential scanning calorimetry to investigate binding to lipid membranes. There was no correlation between MmpL3 binding and or cell activity, suggesting that MmpL3 is not a major target in mycobacteria. However, some of the more active species decreased lipid phase transition temperatures, indicating increased accumulation in membranes, which is expected to lead to enhanced uncoupler activity.
SQ109 是一种结核病候选药物，对具有高活性，被认为至少部分通过抑制 MmpL3 转运蛋白来阻断细胞壁生物合成而发挥作用。它还对缺乏 MmpL3 的细菌和原生动物寄生虫具有活性，在这些寄生虫中，它可以作为解偶联剂，靶向脂膜和 Ca 稳态。在这里，我们合成了 18 种 SQ109 的类似物，并对其进行了测试，以评估它们对 、 、 、 、以及原生动物寄生虫 、 、 、 和 的活性。对分枝杆菌的活性通常低于 SQ109，并且通过增加烷基加合物的大小而降低，但两种类似物对 的活性比 SQ109 高约 4-8 倍，包括一株携带有 MmpL3 中的 A309P 突变的高度耐药菌株。与 SQ109 相比，对其他细菌和原生动物也有更好的活性。特别值得注意的是，我们发现金刚烷基 C-2 乙基、丁基、苯基和苄基类似物对无性血期疟原虫的活性提高了 4-10 倍，同时对人 HepG2 细胞系的毒性较低，这使它们成为新的抗疟药物先导化合物。我们还使用表面等离子体共振研究了抑制剂与 MmpL3 的结合，并使用差示扫描量热法研究了与脂质膜的结合。MmpL3 结合与 或 细胞活性之间没有相关性，这表明 MmpL3 不是分枝杆菌的主要靶标。然而，一些更活跃的物种降低了脂质相转变温度，表明在膜中积累增加，这预计会导致解偶联剂活性增强。
