Toxicological Assessment of Some Synthesized Carbazole Derivatives Using Computational Interaction with CYP2D6 and In Vivo Zebrafish Embryonic Model

Effective management of etiologically complex clinical disorders such as depression usually warrants polypharmacy, a subject of toxicity through drug–drug interactions (DDIs). Metabolism-associated DDI occurs mainly through the irreversible inhibition of the cytochrome P450 (CYP) enzymes, such as CYP2D6, and this affects several marketed antidepressants. From our previous study, an IBScreen database piperazine-linked carbazole derivative (PCD), STOCK3S-94557, was identified as a putative adjuvating/stand-alone antidepressant, suggestively acting through serotonergic pathways. In this study, two PCD analogues, YF1C and YF3A, were synthesized and characterized using GC-MS, 1D and 2D NMR spectroscopy. Their toxicity propensities were studied using in silico interactions with the CYP2D6 enzyme and experimental validation in an in vivo zebrafish embryonic toxicity model. The characterization techniques successfully elucidated the targeted PCDs with a purity of >98%. In the in vivo zebrafish model, YF1C and YF3A imparted no significant toxicity on the embryos at concentrations between 0.5 and 10.0 mg/L. They supported normal hatching, heartbeat rates, and morphological development, without yolk edema and lordosis, following a 96 h post-fertilization exposure to their solutions. These are similar to the effects of the system water and 0.1% DMSO solution (negative controls), while doxorubicin (DOX, positive control) impacted hatching, heartbeats, and morphology, with eventual 100% toxicity-induced mortality. From molecular docking, molecular dynamics, and ADMET predictions, they demonstrated reversible inhibitory interactions and compatibility with the CYP2D6 enzyme, comparable to reference reversible inhibitors (quinidine and ajmalicine), and interesting drug-like properties, implying low tendencies for DDI events. These findings suggest that YF1C and YF3A possess ideal safety for further study as potential drugs.