The excelling role performed by organic chemistry in the medicinal field continues to be one of the main leads in the drug development process. Particularly, the industry requires from organic chemists the discovery of a small molecular structure, which could be a powerful source of pharmacological potential. In this perspective, a diverse range of chalcone (1-11) and aurone (12-22) derivatives were designed and synthesized and for the first time, both motifs were evaluated as potent inhibitors of alkaline phosphatases (APs). The structural identification of the target compounds (1-22) was accomplished by common spectroscopic techniques. The effect of nature and position of substituent was interestingly observed and justified based on their detailed structure-activity relationship (SAR) against AP. It was concluded from the obtained results that all the newly synthesized compounds exhibited high inhibitory potential against AP enzyme. Amongst the series, the compounds 12 (IC50 = 2.163±0.048 M), 15 (IC50 = 2.146±0.056 M), 16 (IC50 = 2.132±0.034 M), 18 (IC50 = 1.154±0.043 M), 20 (IC50 = 1.055±0.029 M) and 21 (IC50 = 2.326±0.059 M) exhibited excellent inhibitory activity against AP, even better/more active than the KH2PO4 (standard) (IC50 = 2.80±0.065 µM). Remarkably, the compound 20 (IC50 = 1.055±0.029 M) may serve as a lead structure to design more potent inhibitors of alkaline phosphatase. To the best of our knowledge, these synthetic compounds have been found the most potent AP inhibitors with minimum IC50 values. Furthermore, molecular modeling study was performed against AP enzyme (1EW2) to check the binding interaction of the synthesized compounds 1-22 against the target protein. Lineweaver-Burk plots demonstrated that most potential derivative 20 inhibition h-IAP via non-competitive pathway. Finally, molecular dynamic (MD) simulations were performed for the evaluation of the dynamic behavior, stability of protein–ligand complex, and binding affinity, resulting in the identification of compound 20 as a potential inhibitor of AP. There is an excellent correlation between experimental and theoretical results.” Pharmacological studies revealed that synthesized analogs 1-22 obey Lipinski\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\'s rule. ADMET parameters assessment showed that these compounds indicate considerable lead-like characteristics with least toxicity and can serve as templates in drug designing.

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