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

Area of Science:

• Mycology and Infectious Diseases
• Medicinal Chemistry
• Toxicology

Background:

• Pythiosis, caused by Pythium insidiosum, is a severe infectious disease with limited treatment options.
• Triazole compounds are explored for their antifungal and antibacterial potential.
• Developing safe and effective treatments for Pythiosis is a critical unmet medical need.

Purpose of the Study:

• To synthesize and evaluate novel triazole compounds for in vitro activity against Pythium insidiosum.
• To assess the safety of these compounds on human leukocytes.
• To predict the pharmacokinetic and toxicological profiles of the synthesized triazoles.

Main Methods:

• Synthesis of three new triazole compounds (C1, C2, C3).
• In vitro susceptibility testing against 15 Pythium insidiosum isolates to determine MIC and MOC.
• Human leukocyte toxicity assays (viability, morphology, oxidative stress).
• In silico ADMET prediction using the pkCSM platform.

Main Results:

• Compounds C1 and C2 demonstrated anti-Pythium insidiosum activity with MIC/MOC ranging from 2 to 64 µg/mL.
• Compound C3 showed MIC from 4-64 µg/mL and MOC from 8-64 µg/mL.
• The triazoles did not induce significant toxicity in human leukocytes, showing no viability loss, morphological changes, or pro-oxidant effects.
• In silico ADMET predictions were comparable to fluconazole.

Conclusions:

• Novel triazole compounds C1, C2, and C3 exhibit significant in vitro activity against Pythium insidiosum.
• These compounds demonstrate a favorable safety profile on human leukocytes at active concentrations.
• The findings support the potential of these triazoles as candidates for Pythiosis treatment.