Bonardi Alessandro, Vermelho Alane Beatriz, da Silva Cardoso Veronica, de Souza Pereira Mirian Claudia, da Silva Lara Leonardo, Selleri Silvia, Gratteri Paola, Supuran Claudiu T, Nocentini Alessio
Department of NEUROFARBA, Pharmaceutical and Nutraceutical Section, University of Florence, Via U. Schiff 6, 50019 Sesto Fiorentino (Firenze), Italy.
Department of NEUROFARBA, Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Firenze, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy.
ACS Med Chem Lett. 2018 Nov 27;10(4):413-418. doi: 10.1021/acsmedchemlett.8b00430. eCollection 2019 Apr 11.
and Leishmania spp. are protozoa of the Trypanosomatidae family, respectively, responsible of the neglected tropical disorders (NTDs) Chagas disease and leishmaniasis. The present pharmacotherapy is often ineffective and exhibits serious side effects. The metalloenzyme carbonic anhydrases (CAs, EC 4.2.1.1) recently identified in these protozoans (α-TcCA and β-LdcCA) are novel promising targets for chemotherapeutic interventions. Herein, we report a series of -nitrosulfonamides, as a novel chemotype to yield the target CA isoform selective inhibition over ubiquitous human isozymes. Two derivatives selected among the most active and selective ones for TcCA/LdcCA over off-target CAs were progressed as silver salts to in vitro studies with various developmental forms and spp of and leishmania. Excellent values of parasites growth inhibition (IC) were observed, with some selectivity index (over cytotoxicity for macrophages and Vero cells) being comparable or better than reference drugs. These findings make -nitrosulfonamides and their salts promising lead compounds for a rational optimization of innovative agents for the treatment of Chagas disease and leishmaniasis based on CA inhibition.
锥虫属和利什曼原虫属分别是锥虫科的原生动物，它们是造成被忽视的热带疾病（NTDs）恰加斯病和利什曼病的病原体。目前的药物治疗往往无效且会产生严重的副作用。最近在这些原生动物中发现的金属酶碳酸酐酶（CAs，EC 4.2.1.1）（α-TcCA和β-LdcCA）是化疗干预的新的有前景的靶点。在此，我们报道了一系列亚硝基磺酰胺，作为一种新型化学类型，对目标CA同工型的抑制作用优于普遍存在的人类同工酶。从对TcCA/LdcCA具有最高活性和选择性的衍生物中挑选出两种，制成银盐，用于对锥虫属和利什曼原虫的各种发育形式进行体外研究。观察到了优异的寄生虫生长抑制（IC）值，一些选择性指数（相对于巨噬细胞和Vero细胞的细胞毒性）与参考药物相当或更好。这些发现使亚硝基磺酰胺及其盐有望成为基于CA抑制作用合理优化治疗恰加斯病和利什曼病创新药物的先导化合物。
