Alkhaldi Abdulsalam A M, de Koning Harry P, Bukhari Syed Nasir Abbas
Biology Department, College of Science, Jouf University, Sakaka, Aljouf, Saudi Arabia.
School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Drug Dev Res. 2025 Feb;86(1):e70055. doi: 10.1002/ddr.70055.
Leishmaniasis and trypanosomiasis are parasitic diseases that are closely linked to poverty, pose significant local burdens, and are common in tropical and subtropical regions. Various synthetic tetralone derivatives were studied as potential scaffolds for antileishmanial and antitrypanosomal activities. The compounds were studied for their effectiveness against multiple kinetoplastid protozoan pathogens: Leishmania major, Leishmania mexicana, and bloodstream trypomastigotes of Trypanosoma brucei brucei. Two different strains of T. b. brucei were used. The first strain was the wild-type Trypanosoma brucei (s427-WT), and the second strain was the multidrug resistant (MDR) strain B48, which was produced by deleting the TbAT1 gene from s427WT and subsequent adaptation to high levels of resistance to diamidines and organo-arsenical drugs. Compounds 4c, 7c, 9b, and 11b showed activity against two strains of Trypanosoma and two different Leishmania species, establishing them as versatile leads with broad anti-kinetoplastid activity. Compound 4c, a tetralone derivative with a bromo-containing trimethoxybenzylidene moiety and methyl-substituted cyclohexanone ring, was identified as the most potent inhibitor for both T. b. brucei strains, with EC values of 0.19 and 0.22 µM for WT and B48, respectively, showing the absence of cross-resistance with the diamidine and arsenical trypanocide classes. In addition, compound 4c exhibited more potency than both controls, eflornithine and pentamidine, against the MDR strain. We conclude that tetralone derivates could be a valuable starting point for the discovery of new antiparasitic drugs.
利什曼病和锥虫病是与贫困密切相关的寄生虫病，在当地造成重大负担，且在热带和亚热带地区很常见。人们研究了各种合成四氢萘衍生物作为抗利什曼原虫和抗锥虫活性的潜在骨架。研究了这些化合物对多种动基体原生动物病原体的有效性：硕大利什曼原虫、墨西哥利什曼原虫以及布氏布氏锥虫的血流型锥鞭毛体。使用了两种不同的布氏布氏锥虫菌株。第一种菌株是野生型布氏锥虫（s427-WT），第二种菌株是多药耐药（MDR）菌株B48，它是通过从s427WT中删除TbAT1基因并随后适应高剂量的双脒类和有机砷类药物而产生的。化合物4c、7c、9b和11b对两种锥虫菌株和两种不同的利什曼原虫物种均表现出活性，使其成为具有广泛抗动基体活性的通用先导化合物。化合物4c是一种具有含溴三甲氧基苄叉部分和甲基取代环己酮环的四氢萘衍生物，被确定为对两种布氏布氏锥虫菌株最有效的抑制剂，对WT和B48的EC值分别为0.19和0.22µM，表明与双脒类和砷剂类锥虫杀灭剂无交叉耐药性。此外，化合物4c对多药耐药菌株的效力比两种对照药物依氟鸟氨酸和喷他脒都更强。我们得出结论，四氢萘衍生物可能是发现新型抗寄生虫药物的有价值的起点。
