New azole-derived hemiaminal ethers as promising acetylcholinesterase inhibitors: synthesis, X-ray structures, in vitro and in silico studies.

A new class of azole-derived hemiaminal ethers is designed as acetylcholinesterase (AChE) inhibitors. The synthesized compounds exhibited remarkable inhibitory activity against acetylcholine. Chiral hemiaminals (3d and 3i) based on (R)-menthoxymethyl group exhibit excellent inhibition with IC50 values of 0.983 ± 1.41 and 1.154 ± 0.89 µM. Similarly, butoxymethyl derivatives 3a, 3f and 3h, also showed promising inhibition comparable to the standard drug, Donepezil. In silico studies were performed to understand the mode of interactions with the target proteins, where menthoxymethyl azoles 3d and 3i demonstrated the highest docking scores. Molecular dynamics simulations displayed the stable ligand-protein complex of 3i with effective binding interactions. The bioavailability and pharmacokinetic parameterssupported the suitability of these small molecule inhibitors to develop cost-effective drug leads for Alzheimer's disease (AD). MTT assay substantiated the non-cytotoxic nature of the compounds. The synthesized compounds are extensively characterized by 1H NMR, 13C NMR and mass spectral data and SC-XRD.Communicated by Ramaswamy H. Sarma.

Identification of two novel thiazolidin-2-imines as tyrosinase inhibitors: synthesis, crystal structure, molecular docking and DFT studies.

Various N- and S-containing 5-membered heterocycles such as imidazole-2-thiones, thiazolidinones and thiazolidin-2-imines are among the most eminent biologically active organic heterocycles and are present in many marketed drugs. In view of their synthetic and biological significance, an efficient synthesis of two novel thiazolidine-2-imines (4a-b) utilizing a three-component one-pot approach starting from an aldimine, an alkyne and isothiocyanates has been developed. The reaction proceeded via a 5-exo digonal (5-exo dig) cyclization of a propargyl thiourea, formed in situ in the presence of Zn(II)-catalyst. The structures of the resulting products are elucidated by spectroscopic methods and X-ray crystallography. A DFT study explored the structural, thermodynamic and molecular electrostatic potential parameters for the compounds. The newly synthesized compounds (4a & 4b) were evaluated for the inhibition of tyrosinase both in vitro and in silico. The in vitro results revealed that the synthesized thiazolidine-2-imines (4a-b) showed good inhibition activity towards mushroom tyrosinase (IC50 = 1.151 ± 1.25 and 2.079 ± 0.87 µM respectively) in comparison to the kojic acid standard (IC50 = 16.031 ± 1.27 µM) a commonly used anti-pigment agent in plant and animal tissues. The experimental inhibition was further assessed by molecular docking studies between synthesized ligands and the human tyrosinase protein complex to investigate the intermolecular interactions responsible for tyrosinase inhibition activity.

Antileishmanial physalins from Physalis minima.

Three new physalins (1-3) and a new withanolide 7 have been isolated from the whole plant of Physalis minima, along with three known physalins: physalin H (4), isophysalin B (5), and 5beta,6beta-epoxyphysalin B (6). Their structures were deduced on the basis of in-depth spectroscopic analyses. Compounds 1-6 showed significant in vitro leishmanicidal activities (0.92-19.4 microg/ml) against promastigotes of Leishmania major.