Nongenotoxic 3-Nitroimidazo[1,2-a]pyridines Are NTR1 Substrates That Display Potent in Vitro Antileishmanial Activity

Twenty nine original 3-nitroimidazo[1,2-a]pyridine derivatives, bearing a phenylthio (or benzylthio) moiety at position 8 of the scaffold, were synthesized. In vitro evaluation highlighted compound 5 as an antiparasitic hit molecule displaying low cytotoxicity for the human HepG2 cell line (CC50 > 100 mu M) alongside good antileishmanial activities (IC50 = 1-2.1 mu M) against L. donovani, L. infantum, and L. major; and good antitrypanosomal activities (IC50 = 1.3-2.2 mu M) against T. brucei brucei and T. cruzi, in comparison to several reference drugs such as miltefosine, fexinidazole, eflornithine, and benznidazole (IC50 = 0.6 to 13.3 mu M). Molecule 5, presenting a low reduction potential (E degrees = -0.63 V), was shown to be selectively bioactivated by the L. donovani type 1 nitroreductase (NTR1). Importantly, molecule 5 was neither mutagenic (negative Ames test), nor genotoxic (negative comet assay), in contrast to many other nitroaromatics. Molecule 5 showed poor microsomal stability; however, its main metabolite (sulfoxide) remained both active and nonmutagenic, making 5 a good candidate for further in vivo studies

Renal collision tumours: three additional case reports

Abstract Background Multiple kidney tumours are frequently seen in hereditary syndromes and familial diseases. Renal collision tumours (RCT) are characterized by the simultaneous existence of different and unrelated tumour types within the same location in the kidney, forming a single, heterogenous lesion. RCT are uncommon histological entities with distinctive features. The most frequent subtypes include clear cell renal cell carcinoma (CCRCC), papillary renal cell carcinoma (PRCC), chromophobe renal cell carcinoma (CRCC), and collecting duct carcinoma (CDC). Case presentation Here, we report three sporadic cases of RCT successfully treated by nephrectomy and confirmed by histological analysis. The first case was of a 64-year-old man diagnosed with RCT composed of a stage 2 nucleolar grade 3 CCRCC and a stage 1a nucleolar grade 2 type 1 PRCC. The second case was of a 68-year-old woman diagnosed with a combined nucleolar grade 2 type 1 PRCC and an angiomyolipoma (non-assessed stage), while the third case was of a 59-year-old woman diagnosed with a combined stage 1a nucleolar grade 3 CCRCC and a stage 1b CDC. Conclusions Due to the rarity of RCT, there are no standard guidelines for their management. Hence, the prognosis is considered to be associated with the most aggressive component, possibly the tumour with the highest nucleolar grade and stage. The histogenesis of RCT remains debated, and increase in knowledge regarding this can help enable the development of targeted therapies for advanced or metastatic tumours