Aucamp Janine, Janse van Rensburg Helena D, Mnyakeni-Moleele Simon S, Suganuma Keisuke, N'Da David D
Centre of Excellence for Pharmaceutical Sciences (Pharmacen), Faculty of Health Sciences, North-West University, Potchefstroom, North West Province, South Africa.
Department of Chemistry, University of Venda, Thohoyandou, Limpopo Province, South Africa.
Drug Dev Res. 2025 Aug;86(5):e70125. doi: 10.1002/ddr.70125.
Diabetes is a fast-growing health issue in low- and middle-income countries, with ~80% of diabetics living in the tropics and sub-tropics. It is a deadly condition claiming the lives of millions of individuals annually, with no therapeutic treatment available to date. The management of diabetes is thus limited to symptomatic relief by glycemic control. Furthermore, the geographical overlap of diabetes and neglected tropical diseases (NTDs) is of concern, as diabetes is known to increase infection susceptibility and severity. In contrast, diabetes-infection comorbidity can negatively affect treatment responses. Leishmaniasis ranks among the top 10 NTDs. Its current therapeutic treatment relies on a handful of drugs that are marred with two main shortcomings: toxicity and reduced efficacy due to pathogenic resistance. Hence, there is a pressing need for new, effective antileishmanial therapeutics. There is evidence of rising cases of leishmaniasis-diabetes co-infection, which may require the use of dual-active therapeutics to curb them. In search of new effective antileishmanial agents with potential for dual use, we evaluated in vitro the antileishmanial and antidiabetic activities of a series of arylidenes derived from hydantoin, glitazone, and rhodanine scaffolds using phenotypic assays, some of which had previously been investigated for antidiabetic potential. Additionally, the antitrypanosomal potential of these compounds was also considered due to the taxonomic relation between Leishmania and Trypanosoma spp. and reported concerns of Chagas disease and human African trypanosomiasis-diabetes comorbidities. Three leishmanicidal early leads with submicromolar activity were uncovered, but no antitrypanosomal or dual leishmaniasis-diabetes active hits were identified.
糖尿病在低收入和中等收入国家是一个快速增长的健康问题，约80%的糖尿病患者生活在热带和亚热带地区。这是一种致命疾病，每年导致数百万人死亡，目前尚无治疗方法。因此，糖尿病的管理仅限于通过血糖控制缓解症状。此外，糖尿病与被忽视热带病（NTDs）的地域重叠令人担忧，因为已知糖尿病会增加感染易感性和严重程度。相反，糖尿病合并感染会对治疗反应产生负面影响。利什曼病位列十大被忽视热带病。其目前的治疗依赖于少数几种药物，这些药物存在两个主要缺点：毒性以及由于病原体耐药性导致疗效降低。因此，迫切需要新的、有效的抗利什曼病治疗药物。有证据表明利什曼病 - 糖尿病合并感染病例在增加，这可能需要使用具有双重活性的治疗药物来控制。为了寻找具有双重用途潜力的新型有效抗利什曼病药物，我们使用表型分析方法在体外评估了一系列源自乙内酰脲（海因）、格列酮和罗丹宁支架的亚芳基化合物的抗利什曼病和抗糖尿病活性，其中一些化合物之前已被研究过抗糖尿病潜力。此外，由于利什曼原虫与锥虫属之间的分类关系以及有关恰加斯病和人类非洲锥虫病 - 糖尿病合并症的报道担忧，还考虑了这些化合物的抗锥虫潜力。发现了三种具有亚微摩尔活性的抗利什曼病早期先导化合物，但未鉴定出抗锥虫或具有双重利什曼病 - 糖尿病活性的命中化合物。
