Monoamine oxidase-B (MAO-B), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) have been considered target enzymes of depression and neurodegenerative diseases, including Alzheimer’s disease (AD). In this study, seventeen N-methyl-piperazine chalcones were synthesized, and their inhibitory activities were evaluated against the target enzymes. Compound 2k (3-trifluoromethyl-4-fluorinated derivative) showed the highest selective inhibition against MAO-B with an IC50 of 0.71 μM and selectivity index (SI) of 56.34, followed by 2n (2-fluoro-5-bromophenyl derivative) (IC50 = 1.11 μM, SI = 16.04). Compounds 2k and 2n were reversible competitive MAO-B inhibitors with Ki values of 0.21 and 0.28 μM, respectively. Moreover, 2k and 2n effectively inhibited AChE with IC50 of 8.10 and 4.32 μM, which underscored their multi-target inhibitory modes. Interestingly, compound 2o elicited remarkable inhibitions over MAO-B, AChE, and BChE with IC50 of 1.19–3.87 μM. A cell-based assay of compounds 2k and 2n against Vero normal cells pointed out their low cytotoxicity. In a docking simulation, 2k showed the lowest energy for MAO-B (−11.6 kcal/mol) with four hydrogen bonds and two π-π interactions. Furthermore, in silico studies were conducted, and disclosed that 2k and 2n are expected to possess favorable pharmacokinetic properties, such as the ability to penetrate the blood–brain barrier (BBB). In view of these findings, compounds 2k and 2n could serve as promising potential candidates for the treatment of neurodegenerative diseases.
A new series of 3,4,5-trimethoxyphenyl thiazole pyrimidines has been synthesized and biologically evaluated for its in vitro anticancer activity. Compounds 4a, 4b, and 4h with substituted piperazine showed the best antiproliferative activity. In the NCI-60 cell line screening, compound 4b showed promising cytostatic activity against multiple cell lines. Notably, it elicited a GI value of 86.28% against the NSCL cancer cell line HOP-92 at a 10 μM dose. Compounds 4a and 4h at 10 μM showed promising GI values of 40.87% and 46.14% against HCT-116 colorectal carcinoma and SK-BR-3 breast cancer cell lines, respectively. ADME-Tox prediction of compounds 4a, 4b, and 4h revealed their acceptable drug-likeness properties. In addition, compounds 4a, 4b, and 4h showed a high probability of targeting kinase receptors via Molinspiration and Swiss TargetPrediction.
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