Chalcones bearing nitrogen-containing heterocyclics as multi-targeted inhibitors: Design, synthesis, biological evaluation and molecular docking studies

In this work, a series of chalcones (1a–d, 2a–d, 3a–d, 4a–d, and 5a–d) were designed and synthesized by Claisen–Schmidt condensation. Also, their chemical structures were elucidated using UV–Vis, FT IR, ¹H NMR, ¹³C NMR, MS spectral data, and elemental analyses. Subsequently, the anticholinesterase, tyrosinase, urease inhibitory activities and antioxidant activities of all chalcones were evaluated. The inhibitory potential of all chalcones in terms of IC₅₀ value was observed to range from 7.18 ± 0.43 to 29.62 ± 0.30 μM against BChE by comparing with Galantamine (IC₅₀ 46.06 ± 0.10 μM) as a reference drug. Also, compounds 2c, 3c, 4c, 4b, and 4d exhibited high anticholinesterase activity against both AChE and BChE enzymes. The tyrosinase inhibitory activity results revealed that three compounds (IC₅₀ 1.75 ± 0.83 μM for 2b, IC₅₀ 2.24 ± 0.11 μM for 3b, and IC₅₀ 1.90 ± 0.64 μM for 4b) displayed good inhibitory activity against tyrosinase compared with kojic acid (IC₅₀ 0.64 ± 0.12 μM). In addition, other different three chalcones (IC₅₀ 22.34 ± 0.25 μM for 2c, IC₅₀ 20.98 ± 0.08 μM for 3c, and IC₅₀ 18.26 ± 0.13 μM for 4c) showed excellent inhibitory activity against the urease by comparing with thiourea (IC₅₀ 23.08 ± 0.19 μM). Compounds 3c and 4c showed the best potency in all antioxidant activity tests. In light of these findings, the structure–activity relationship for compounds was also described. Furthermore, molecular modeling studies, including molecular docking, absorption, distribution, metabolism, excretion, and toxicity (ADMET), and pharmacophore analyses of compounds, gave important information about the interactions and drug-likeness properties. As a result, all chalcones exhibited suitable ADMET findings, predicting good oral bioavailability.