Novel drug development is onerous, time consuming and overpriced process with particularly low success and relatively high enfeebling rates. To overcome this burden, drug repositioning approach is being used to predict the possible therapeutic effects of FDA approved drugs in different diseases. Herein, we designed a computational and enzyme inhibitory mechanistic approach to fetch the promising drugs from the pool of FDA approved drugs against AD. The binding interaction patterns and conformations of screened drugs within active region of AChE were confirmed through molecular docking profiles. The possible associations of selected drugs with AD genes were predicted by pharmacogenomics analysis and confirmed through data mining. The stability behaviour of docked complexes (Drugs-AChE) were checked by MD simulations. The possible therapeutic potential of repositioned drugs against AChE were checked by in vitro analysis. Taken together, Cinitapride displayed a comparable results with standard and can be used as possible therapeutic agent in the treatment of AD.

A series of symmetrical salicylaldehyde-bishydrazine azo molecules, 5a–5h, have been synthesized, characterized by ¹H-NMR and ¹³C-NMR, and evaluated for their in vitro α-glucosidase and α-amylase inhibitory activities. All the synthesized compounds efficiently inhibited both enzymes. Compound 5g was the most potent derivative in the series, and powerfully inhibited both α-glucosidase and α-amylase. The IC₅₀ of 5g against α-glucosidase was 0.35917 ± 0.0189 µM (standard acarbose IC₅₀ = 6.109 ± 0.329 µM), and the IC₅₀ value of 5g against α-amylase was 0.4379 ± 0.0423 µM (standard acarbose IC₅₀ = 33.178 ± 2.392 µM). The Lineweaver-Burk plot indicated that compound 5g is a competitive inhibitor of α-glucosidase. The binding interactions of the most active analogues were confirmed through molecular docking studies. Docking studies showed that 5g interacts with the residues Trp690, Asp548, Arg425, and Glu426, which form hydrogen bonds to 5g with distances of 2.05, 2.20, 2.10 and 2.18 Å, respectively. All compounds showed high mutagenic and tumorigenic behaviors, and only 5e showed irritant properties. In addition, all the derivatives showed good antioxidant activities. The pharmacokinetic evaluation also revealed promising results

Sulfonamide derivatives serve as an important building blocks in the drug design discovery and development (4D) process. Ciprofloxacin-, sulfadiazine- and amantadine-based sulfonamides were synthesized as potent inhibitors of jack bean urease and free radical scavengers. Molecular diversity was explored and electronic factors were also examined. All 24 synthesized compounds exhibited excellent potential against urease enzyme. Compound 3e (IC₅₀ = 0.081 ± 0.003 µM), 6a (IC₅₀ = 0.0022 ± 0.0002 µM), 9e (IC₅₀ = 0.0250 ± 0.0007 µM) and 12d (IC₅₀ = 0.0266 ± 0.0021 µM) were found to be the lead compounds compared to standard (thiourea, IC₅₀ = 17.814 ± 0.096 µM). Molecular docking studies were performed to delineate the binding affinity of the molecules and a kinetic mechanism of enzyme inhibition was propounded. Compounds 3e, 6a and 12d exhibited a mixed type of inhibition, while derivative 9e revealed a non-competitive mode of inhibition. Compounds 12a, 12b, 12d, 12e and 12f showed excellent radical scavenging potency in comparison to the reference drug vitamin C.

Structurally diverse adamantyl-iminothiazolidinone conjugates were synthesized, evaluated for elastase inhibition, and subjected to in silico ADMET prediction. The inhibition studies revealed compounds 5a, 5f, 5g, and 5h to show significant activity.