In silico estimation and analysis of bioavailability, pharmacokinetics and toxicological properties of selected piperazine derivatives

Abstract

Piperazine is a flexible heterocyclic scaffold widely employed in drug design due to its ability to interact with diverse biological targets. This study computationally assesses the bioavailability, pharmacokinetic, and toxicological properties of its derivatives (1-27), with compounds 1-4 being commercially available drugs. Drug-likeness parameters were calculated using the SwissADME web tool and MoloVol software (v1.2.0). The SwissADME web tool predicted gastrointestinal absorption, blood–brain barrier permeability, P-glycoprotein recognition, and CYP450 inhibition. Toxicological profiles were assessed with DataWarrior software (v06.05.04), classifying compounds as mutagenic, carcinogenic, reproductive toxins and irritants. Based on Lipinski’s rule, all compounds except 17 and 19 are predicted to have favourable absorption and permeability. All com pounds (except 9) exhibited TPSA < 140 Ų, indicating good intestinal absorption, while compounds 2, 4–6, 11–13, 16–18, 23–25, and 27 displayed TPSA < 60 Ų, suggesting blood–brain barrier penetration. Most compounds (1–4, 7–9, 14, 16, 17, 19–25) were predicted to be P-glycoprotein substrates. Metabolic profiling indicated inhibition of multiple CYP450 isoenzymes, including 1A2, 2C19, 2C9, 2D6, and 3A4. None of the compounds exhibited mutagenic risk. Carcinogenicity was observed for compounds 5 and 13. Reproductive toxicity was detected for compounds 6, 12, and 14. Irritant effects were present for compounds 11–15. After careful consideration of all findings, further in vitro and in vivo studies are recommended to evaluate the compounds as potential new antiparasitic (7, 8, 10), antimicrobial (11), neuroactive (16), anti inflammatory (18, 20–24), antitubercular (25, 26), and antitumor (27) agents.