Carboxylate derivatives of tributyltin (IV) complexes as anticancer and antileishmanial agents

BACKGROUND: Tributyltin (IV) compounds are promising candidates for drug development. In the current study, we evaluated in-vitro and in-silico profile of carboxylate derivatives of tributyltin (IV) complexes. METHODS: ADMET and drug-likeliness properties were predicted using MetaPrint2D React, preADMET, SwissADME and Molsoft tools. SwissTargetPrediction predicted molecular targets for compounds. In-vitro bioactivity was evaluated by quantifying cytotoxicity against HepG2, THP-1 cell lines, isolated lymphocytes and leishmania promastigotes as well as measuring protein kinase (PK) inhibition activity. RESULTS: Results indicate partial compliance of compounds with drug-likeliness rules. Ch-409 complies with WDI and Lipinski rules. ADMET profile prediction shows strong plasma protein binding except for Ch-409, low to high GI absorption and BBB penetration (C(brain)/C(blood) = 0.942–11; caco-2 cells permeability 20.13–26.75 nm/sec), potential efflux by P-glycoprotein, metabolism by CYP3A4, medium inhibition of hERG, mutagenicity and capacity to be detoxified by glutathionation and glucuronidation. Molecular targets include proteases, enzymes, membrane receptors, transporters and ion channels where Ch-409 targets membrane receptors only. Compounds are significantly (p < 0.05) cytotoxic against HepG2 cell line and leishmania as compared with normal isolated lymphocytes. Ch-459 indicates highest toxicity against leishmania (mortality 97.9 ± 3.99%; LC50 0.323 ± 0.002 μg/mL) whereas Ch-409 possesses maximum cytotoxicity against HepG2 cell line (IC50 0.08 ± 0.001 μg/mL) as well as 97.5 ± 1.98% (LC50 0.954 ± 0.158 μg/mL) mortality of leishmania promastigotes. It was observed that antileishmanial effect was reduced by 16.38%–34.38% and 15–38.2% in the presence of NaN(3) and mannitol respectively. PK inhibition and reactive oxygen species production are possible mechanisms for cytotoxicity. CONCLUSIONS: Selected carboxylate derivatives of tributyltin (IV) complexes possess significant antileishmanial and cytotoxic potential. These are promising compounds for the development of antileishmanial and anticancer drugs. [Figure: see text]