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In this study, 1‐(4‐substitued benzyl)‐3,5‐diphenyl‐1H‐1,2,4‐triazoles (2 a‐e) and ethyl(3,5‐diphenyl‐1H‐1,2,4‐triazole‐1‐yl)acetate (3) were synthesized starting from 3,5‐diphenyl‐1H‐1,2,4‐triazole (1). The ethyl acetate derivative (3) was converted to 2‐(3,5‐diphenyl‐1H‐1,2,4‐triazole‐1‐yl)acetohydrazide (4) in ethanolic medium with hydrazine hydrate. The reaction of the acetohydrazide (4) with suitable isothiocyanates generate 2‐[(3, 5‐diphenyl‐1H‐1,2,4‐triazole‐1‐yl)acetyl]‐4‐methyl/phenyhlthiosemicarbazide (5 a,b). The cyclization of the thiosemicarbazide (5 a,b) in the presence of NaOH (2 M) resulted in the formation of 5‐[(3, 5‐diphenyl‐1H‐1,2,4‐triazole‐1‐yl)methyl]‐4‐methyl/phenyl‐2,4‐dihidro‐3H‐1,2,4‐triazole‐3‐thiol (6 a,b). Finally, the synthesized 1,2,4‐triazole‐3‐thiols (6 a,b) were converted to their S‐substituebenzyl derivatives (7 a‐j). All of the synthesized compounds (1‐7) were also examined for antioxidant capacities, and antiurease and anti‐acetylcholinesterase (anti‐AChE) activities. It has been found that antioxidant capacity and anti‐urease activity of the compound 7 f is very good in biochemically active compounds.

Tyrosinase inhibition is very important in controlling melanin synthesis. If melanin synthesis is not controlled in metabolism, an unwanted increase in melanin synthesis occurs. As melanin plays a role in the formation of skin color, its unusual levels cause some skin disorders such as pregnancy scars, age spots, and especially skin cancer (melanoma). However, the tyrosinase activity is also related to Parkinson's disease and some neurodegenerative diseases. For all these reasons, the medicinal as well as the cosmetic industries focus on research on tyrosinase inhibitors for the treatment of skin disorders and some neurodegenerative diseases. In this study, 32 new 1,2,4‐triazole–(thio)semicarbazide hybrid molecules (6a–p and 7a–p) were synthesized, starting from 4‐amino‐1‐pentyl‐3‐phenyl‐1H‐1,2,4‐triazole‐5(4H)‐one. These compounds were evaluated for their inhibitory activity against mushroom tyrosinase. The results indicated that 6h, 6m, 6n, and 6p exhibited the most effective inhibitory activity, with IC50 values of 0.00162 ± 0.0109, 0.00166 ± 0.0217, 0.00165 ± 0.019, and 0.00197 ± 0.0063 μM, respectively, compared with kojic acid as the reference drug (IC50 = 14.09 ± 0.02 μM). Also, molecular docking analyses were performed to suggest possible binding poses for the ligands. As a result, derivatives 6h, 6m, 6n, and 6p can be used as promising tyrosinase inhibitor candidates in the medicinal, cosmetics, or food industries.

Two series of 1,3,4‐thiadiazole (40a–o) and 1,2,4‐triazole‐5‐thione (41a–l) derivatives bearing a 2‐pentyl‐5‐phenyl‐1,2,4‐triazole‐3‐one ring were synthesized and then studied for their urease inhibitory activities using thiourea as a standard drug. Among the two groups, the first group (40a–o) did not show good activity while the second group (41a–l) showed excellent activity. Compound 41j (1091.24 ± 14.02 µM) of the second series of compounds showed lower activity than thiourea, while the remaining 11 compounds (41a–i, k, and l) showed better activity than thiourea (183.92 ± 13.14 µM). Among the 11 compounds, 41b (15.96 ± 2.28 µM) having the 3‐F group on the phenyl ring showed the highest inhibitory activity. Urease kinetic studies of 41b, which is the most active compound, determined it to have an un‐competitive inhibition potential. Moreover, in silico analysis against urease from jack bean with 27 new heterocyclic compounds and the reference molecule was carried out to see the necessary interactions responsible for urease activity. The docking calculations of all compounds supported stronger binding to the receptor than the reference molecule, with high inhibition constants. In addition, compound 40m was characterized by single‐crystal X‐ray diffraction analysis. X‐ray analysis reveals that the structures of the compound 40m crystallize in the monoclinic P21/c space group with the cell parameters: a = 10.2155(9) Å, b = 22.1709(18) Å, c = 21.4858(17) Å, β = 99.677(8)°, V = 4797.0(7) Å3. X‐ray diffraction analyses were also performed to gain insights into the role of weak intermolecular interactions and C‐H…X (halogen) interactions in compound 40m that influence the crystal packing.

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