A Broad Spectrum Antiparasitic Activity of Organotin (IV) Derivatives and Its Untargeted Proteomic Profiling Using Leishmania donovani

• Published in: Pathogens (Basel) 2022-11, Vol.11 (12), p.1424
• Main Authors: Hayat, Obaid, Ullah, Nazif, Sirajuddin, Muhammad, Giardini, Miriam A, Nguyen, Jennifer V, Francisco, Karol R, Liu, Lawrence J, Sun, Yujie Uli, Maurya, Svetlana, McGrosso, Dominic, Gonzalez, David J, Caffrey, Conor R, Debnath, Anjan, Siqueira-Neto, Jair L
• Format: Article
• Language: English
• Subjects: Amastigotes; Antibiotics; antiparasitic activity; Antiparasitic agents; Arsenic; Automation; Bacterial infections; Chemistry; Coordination compounds; Cytotoxicity; drug discovery; Endosomes; Giardia; Heavy metals; Infections; Intracellular; Kidneys; Leishmania donovani; Medical importance; Metal complexes; Metals; Monocytes; Myoblasts; neglected tropical diseases; Optimization; organotin (IV) compounds; Organotin compounds; Parasites; Pathogens; Promastigotes; Proteomics; Protozoa; Schistosoma mansoni; Selectivity; Toxicity
• ISSN: 2076-0817; 2076-0817
• DOI: 10.3390/pathogens11121424

Metals have been used in medicine since ancient times for the treatment of different ailments with various elements such as iron, gold and arsenic. Metal complexes have also been reported to show antibiotic and antiparasitic activity. In this context, we tested the antiparasitic potential of 10 organotin (IV) derivatives from 4-(4-methoxyphenylamino)-4 oxobutanoic acid (MS26) against seven eukaryotic pathogens of medical importance: , , , , , and . Among the compounds with and without antiparasitic activity, compound MS26Et3 stood out with a 50% effective concentration (EC ) of 0.21 and 0.19 µM against promastigotes and intracellular amastigotes of respectively, 0.24 µM against intracellular amastigotes of , 0.09 µM against 1.4 µM against and impaired adult viability at 1.25 µM. In terms of host/pathogen selectivity, MS26Et3 demonstrated relatively mild cytotoxicity toward host cells with a 50% viability concentration of 4.87 µM against B10R cells (mouse monocyte cell line), 2.79 µM against C2C12 cells (mouse myoblast cell line) and 1.24 µM against HEK923 cells (human embryonic kidney cell line). The selectivity index supports this molecule as a therapeutic starting point for a broad spectrum antiparasitic alternative. Proteomic analysis of host cells infected with after exposure to MS26Et3 showed a reduced expression of Rab7, which may affect the fusion of the endosome with the lysosome, and, consequently, impairing the differentiation of to the amastigote form. Future studies to investigate the molecular target(s) and mechanism of action of MS26Et3 will support its chemical optimization.