Based on tyrosinase inhibition science, two pyrimidine derivatives were designed and studied. Docking of 2-dibenzylamine-5-hydroxy pyrimidine (dba5HP) and 2-benzylamino-5-hydroxy pyrimidine (ba5HP) on mushroom tyrosinase (MT) showed that the former could not occupy MT active site pocket, while ba5HP could do so (Moldock score = − 63.95). MD simulation revealed that the complex of ba5HP-MT reached stability < 30 ns. In silico biocompatibility examinations predicted high permeability, good bioavailability, low toxicity, and synthetic accessibility of 1.59 for ba5HP with high probability for CYP-mediated metabolism. Subsequently, both compounds were synthesized in good yields. Kinetics studies proved that, unlike dba5HP, ba5HP could strongly inhibit MT competitively (IC50 = 32.28, Ki = 11.32 μM). Considering the facile synthesis, potential for structural modifications, and passing most of the lead-likeness filters, it seems likely that ba5HP plays key roles in the syntheses of novel depigmentation medicines as well as more specific inhibitors for various tyrosinases and polyphenol oxidases.

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