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    Identification of hCA I, hCA II, AChE and BChE Inhibitory Properties of Some Norcantharimide Derivatives; Molecular Docking, SAR and in silico ADME Studies
    (Wiley-V C H Verlag Gmbh, 2024) Kose, Leyla Polat; Kose, Aytekin
    (3aR,4S,7R,7aS)-2-Alkyl/aryl-3a,4,7,7a-tetrahydro-1H-4,7-epoxyisoindole-1,3(2H)-diones, which are norcantharimide derivatives, were synthesized and their effects on carbonic anhydrase I (hCA I) and II (hCA II), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibitory activity were investigated. For enzyme activity studies, hCA I and II isoenzymes purified from human erythrocytes and the commercially available enzymes AChE and BChE, which are both markers and significantly affect the known symptoms of Alzheimer's disease, were used. The two derivatives exerted efficient inhibition with IC50=4.530 nM (Ki=4.483) and 4.426 nM (Ki=4.696) against hCA I and with IC50=3.825 nM (Ki=3.854) and 3.457 nM (Ki=3.292) against hCA II, respectively. The another two derivatives exerted considerable inhibition with IC50=0.526 nM (Ki=0.224) and 0.575 nM (Ki=0.292) against AChE and with IC50=0.135 nM (Ki=0.057) and IC50=0.180 nM (Ki=0.070) against BChE, respectively. The compounds showed activity at the nanomolar level. These remarkable inhibition results were compared with those of standard inhibitors (acetazolamide for hCA I and II and tacrine for AChE and BChE) of each enzyme, reported, and graphed. In addition, molecular docking studies were carried out by in silico methods and the structure-activity relationship was discussed. The poses of compound 4 c are presented along with the ligand-receptor interaction against all metabolic enzymes. Inhibition activity studies of some norcantharimide derivatives were carried out on hCA I and II, AChE, and BChE enzymes. It was found that the inhibition results had values that were similar to the standards. In addition, molecular docking studies of the N-Ph-norcantharimide derivative were carried out and the structure-activity relationship was elucidated. image
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    New 4-methanesulfonyloxy benzohydrazide derivatives as potential antioxidant and carbonic anhydrase I and II inhibitors: synthesis, characterization, molecular docking, dynamics & ADME studies
    (Elsevier, 2025) Kose, Aytekin; Kose, Leyla Polat; Senol, Halil; Ulusoy-Guzeldemirci, Nuray
    As an archetypal molecule, hydrazides have a crucial vital role in numerous applications, so hydrazide-related inhibitors, especially sulfur-enriched, are favored. In the present work, we designed, synthesized and characterized fifteen novel benzohydrazide derivatives containing 4-methanesulfonyloxy and arylidene building blocks with a four-step synthesis pathway. The inhibitory potential of the compounds was assessed using human carbonic anhydrases I and II (hCA I and II) isozymes and the results were compared to those of the standard inhibitor, acetazolamide (AZA). The antioxidant activity profiles for all compounds were also examined using various bioanalytical methods and the results were compared with the standards. The hCA I and II were the best inhibited by compounds 5f, 5g, and 5i with inhibition constants IC50 in the range 20.45-51.43 nM (AZA: IC50=218.38) for hCA I and 33.54-42.45 nM (AZA: IC50=44.39) for hCA II. Structure-activity relationships were also discussed and discovered that hCA I and II inhibition was unaffected by the presence of an electronwithdrawing or releasing group. This effectiveness was the only result of the sort of substituted group(s), which was located at the reagent. Molecular docking and dynamics simulations showed that compounds 5f, 5g, and 5i have strong and stable interactions with key amino acids and zinc ions in the active sites of enzymes, which supports their ability to block enzyme activity. In silico ADME studies predicted favorable drug-like properties and high human oral absorption for all synthesized compounds. In silico ADME studies predicted favorable drug-like properties and high human oral absorption for all synthesized compounds. These findings highlight the multifunctional potential of the synthesized benzohydrazide derivatives as hCA I and II inhibitors and antioxidants, paving the way for their further development and optimization for therapeutic applications.