Evaluation of ortho-substituted Bis-Functionalized Triazoles as Tyrosinase Inhibitors: Modulating Dopamine Synthesis and Behavior in Zebrafish

AbstractFacile and green chemistry pathways are utilized through microwave-assisted organic synthesis (MAOS) to generate biologically activeortho-substituted bis-functionalized triazole derivatives (C1-C7) in one step. MAOS expedited the process by improving reaction times (from 24  hours to 15–20 minutes) and provided the triazoles with good to excellent yields. Zebrafish based physiological and morphological analyses were carried out and most synthesized triazole compounds showed a significantly increased heart rate and growth in Zebrafish. The maximum tolerable dose ( MTD) of these compounds were identified to be 2 µM. Importantly, the methoxy functionalized triazole (C7) compound induced loss of pigmentation in zebrafish larvae by inhibiting tyrosinase enzyme and subsequently blocking melanin synthesis. Since tyrosinase enzyme is also involved in dopamine synthesis, investigations onC7 were carried out to check if it could impair dopamine synthesis and thereby affect behavior. In addition,C7 was found to reduce dopamine synthesis in the retinal ganglion neurons and consequently increase light sensitivity in the dark-adapted zebrafish larvae. Thus,C7 (ortho-methoxy) has been identified as a novel tyrosinase inhibiting triazole derivative that can modulate dopamine levels in the neural circuit resulting in altered behavior.
Source: Medicinal Chemistry Research - Category: Chemistry Source Type: research