Anti-Pythium insidiosum activity of three novel triazole compounds: synthesis, pharmacokinetic and toxicological parameters

Abstract

Pythiosis, caused by Pythium insidiosum, is an infectious and non-transmissible disease affecting horses, dogs, and humans, with no effective drug treatment available. Triazoles are compounds of interest for their potential pharmacological properties against fungi and bacteria. In this study, we synthesized three new triazole compounds (C1, C2, and C3) to assess their in vitro activities against P. insidiosum and their safety on human leukocytes. Susceptibility testing was performed against P. insidiosum isolates (n = 15) to determine the minimum inhibitory concentration (MIC) and minimum oomicidal concentration (MOC). The leukocyte toxicity of triazoles was evaluated by measuring cell viability, morphological aspects, and oxidative stress endpoints. In silico prediction of the compounds absorption, distribution, metabolism, excretion and toxicity (ADMET) was determined using the pkCSM platform. Both triazoles C1 and C2 exhibited anti-Pythium insidiosum activity at concentrations from 2 to 64 µg/mL to MIC and MOC, while C3 MIC was 4-64 µg/mL and MOC 8-64 µg/mL. The three compounds did not induce viability loss and/or morphologic changes to human leukocytes, and showed absence of a pro-oxidant profile. ADMET properties prediction of the compounds was similar to the reference drug fluconazole. This study introduces novel triazole compounds exhibiting anti-P. insidiosum activity at concentrations non-toxic to human leukocytes.

Keywords: Azoles; Human leukocytes; Pythiosis; Susceptibility tests; Toxicity.