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.

Hydrazine clubbed 1,3-thiazoles as potent urease inhibitors: design, synthesis and molecular docking studies.

Synthesis of a novel series of hydrazine clubbed 1,3-thiazoles (5a-m) has been described by reacting hydrazine-1-carbothioamides (3a-k) with α-chloro- or bromo-acetophenones (4a-d) in refluxing ethanol in good to excellent yields (65-86%). Structural confirmation was based upon spectroscopic techniques such as 1H-NMR, 13C-NMR, FT-IR and mass spectrometry. The biological application of these motifs has been demonstrated in terms of their strong urease inhibition activity. The results of in vitro study revealed that all the compounds are the potent inhibitors of urease. The IC50 (ranging in between 110 and 440 nM) values were higher as compared to that of standard, i.e., thiourea (IC50 = 490 ± 10 nM). The synthesized compounds were docked at the active sites of the Jack bean urease enzyme in order to explore the possible binding interactions of enzyme-ligand complexes; the results reinforced the in vitro biological activity results.

Bis-Schiff bases of 2,2'-dibromobenzidine as efficient corrosion inhibitors for mild steel in acidic medium.

In this work, three new bis-Schiff bases, namely 1,1'-(2,2'-dibromo-[1,1'-biphenyl]-4,4'-diyl)bis(N-phenylmethanimine) (BNSB01), 1,1'-(2,2'-dibromo-[1,1'-biphenyl]-4,4'-diyl)bis(N-(4-bromophenyl)methanimine) (BNSB02) and 4,4'-(((2,2'-dibromo-[1,1'-biphenyl]-4,4'-diyl)bis(methanylylidene))bis(azanylylidene))diphenol (BNSB03), were synthesized. These Schiff bases were evaluated for their corrosion inhibition ability on mild steel specimens in 0.5 M HCl by using electrochemical and weight loss techniques. The inhibition performance was found to increase with an increase in the inhibitor concentration and decrease with an increase in temperature. The results revealed that the synthesized compounds followed the Langmuir isotherm model and were efficient mixed-type inhibitors. The electrochemical impedance studies also indicated that with a rise in the concentration of inhibitors, the charge transfer resistance increased. The surface morphology of the inhibited and uninhibited specimens was examined using scanning electron microscopy (SEM). The efficiency of the compounds was in the order BNSB02 > BNSB03 > BNSB01. All the results obtained were in good correlation with each other.

Synthesis, antibacterial activity and molecular docking study of vanillin derived 1,4-disubstituted 1,2,3-triazoles as inhibitors of bacterial DNA synthesis.

Antimicrobial resistance (AMR) compelled scientists in general while pharmacists, chemists and biologists in specific to believe that we could always remain ahead of the pathogens. The pipeline of new drugs is running gasping and the inducements to develop new antimicrobials to address the global problems of drug resistance are weak. In this pursuit, effective endeavours to prepare new anti-bacterial entities is highly wished. The present study demonstrates successful synthesis of a library of 1,4-disbustituted 1,2,3-triazoles (3a-3k) using Click-chemistry concept and anti-their bacterial potential. In this 1,3-dipolar cycloaddition, the 3-methoxy-4-(prop-2-yn-1-yloxy)benzaldehyde (1) was used as alkyne partner which was synthesized from vanillin and propargyl bromide and further reacted with differently substituted arylpropoxy azides (2a-k) to furnish series of mono and bis1,4-disubstituted-1,2,3-triazoles. All the synthesized compounds were characterized spectroscopically and were evaluated for their initial antimicrobial activity. Preliminary results of antibacterial screening revealed that the synthesized compounds have the highest inhibitory effects compare to the control ciprofloxacin. The compounds 3b and 3g were found to be the most active (MIC: 5 µg/mL, MIC: 10 µg/mL respectively) against various strains of gram-positive and gram-negative bacteria. The molecular docking study against 4GQQ protein with synthesized ligands was performed to see the necessary interactions responsible for anti-bacterial activity. The docking analysis of the most potent compound 3g supported the antibacterial activity exhibiting high inhibition constant and binding energy.

Synthesis, Crystal Structure, Hirshfeld Surface Analysis, DFT, and DNA-Binding Studies of (E)-2-(3-Hydroxy-4-Methoxybenzylidene)Hydrazinecarbothioamide.

(E)-2-(3-Hydroxy-4-methoxybenzylidene)hydrazinecarbothioamide 3 was synthesized by reacting thiosemicarbazide with 2-hydorxy-3-methoxybenzaldehyde in dry ethanol. The structure was elucidated by spectroscopic (FT-IR, 1H NMR, and 13C NMR) and single crystal X-ray diffraction techniques. A detailed analysis of the intermolecular interactions has been performed based on the Hirshfeld surfaces and their associated two-dimensional fingerprint plots. DFT, spectroscopic, and electrochemical DNA-binding analysis confirmed that the compound is reactive to bind with DNA. Viscometric studies suggested that compound 3 has a mixed mode of interaction and intercalated into the DNA base pairs predominantly along with the possibility of electrostatic interactions. Graphical Abstract.

One-pot four-component synthesis of thiazolidin-2-imines using CuI/ZnII dual catalysis: A new class of acetylcholinesterase inhibitors.

An efficient one-pot four-component strategy involving aldehydes, amines, alkynes and isothiocyanates has been developed to access a novel series of thiazolidine-2-imines (5a-x). This process operates under the action of a cooperative catalysis composed of Cu(I) and Zn(II) delivering the desired five-membered heterocyclic compounds in good to excellent yields. Notably, this transformation avoids the use of pre-formed imines or propargylamines and proceeds via an intramolecular 5-exo-dig hydrothiolation reaction of the in situ formed propargyl thiourea. Furthermore, the biological application of these motifs was demonstrated in terms of their strong acetylcholinesterase (AChE) inhibitory activity where compound 5s was identified as the lead AChE inhibitor with an IC50 value of 0.0023 ±â€¯0.0002 µM, 88-folds stronger inhibition than standard drug (neostigmine methyl sulphate; IC50 = 0.203 ±â€¯0.004 µM). Molecular docking analysis reinforced the in vitro biological activity results revealing the formation of several useful interactions of the potent lead with amino acid residues in the active site of the enzyme.

Developing hybrid molecule therapeutics for diverse enzyme inhibitory action: Active role of coumarin-based structural leads in drug discovery.

Hybrid drugs featuring two or more potentially bioactive pharmacophores have been recognized as advanced and superior chemical entities to simultaneously modulate multiple drug targets of multifactorial diseases, thus overcoming the severe side effects associated with a single drug molecule. The selection of these chemical moieties to produce hybrid structures with druggable properties is generally facilitated by the observed and/or anticipated synergistic pharmacological activities of the individual molecules. In this perspective, coumarin template has extensively been studied in pursuit of structurally diverse leads for drug development due to high affinity and specificity to different molecular targets. This review highlights the most commonly exploited approaches conceptualizing the design and construction of hybrid molecules by coupling two or more individual fragments with or without an appropriate linker. In addition to the design strategies, this review also summarizes and reflects on the therapeutic potential of these hybrid molecules for diverse enzyme inhibitory action as well as their observed structure-activity relationship (SAR). Several key features of the synthesized hybrid structures that assert a profound impact on the inhibitory function have also been discussed alongside computational investigations, inhibitor molecular diversity and selectivity toward multiple drug targets. Finally, these drug discovery and development efforts should serve as a handy reference aiming to provide a useful platform for the exploration of new coumarin-based compounds with enhanced enzyme inhibitory profile.

Synthesis of highly functionalized 1,6-dihydropyridines via the Zn(OTf)2-catalyzed three-component cascade reaction of aldimines and two alkynes (IA2-coupling).

A zinc(ii) triflate catalyzed three component synthesis of 1,6-dihydropyridines, involving aldimines, alkynes and electron-deficient dimethyl acetylenedicarboxylate (DMAD), in good to excellent yields has been described. Besides a range of different N-substituents, a variety of both aromatic and aliphatic alkynes could be used. The application of electron-deficient propiolates instead of DMAD resulted in regiospecific incorporation of the ester functionality on the 1,6-dihydropyridine ring. The reaction proceeds via a cascade reaction involving nucleophilic addition of the metal acetylide to the imine, followed by the addition of the intermediately formed propargylic amine to the electron-deficient alkyne and subsequent 6-endo dig cyclization.

Synthesis, in vitro and computational studies of 1,4-disubstituted 1,2,3-triazoles as potential α-glucosidase inhibitors.

1,4-Disubstituted-1,2,3-triazoles were synthesized by Cu(I) catalyzed click reaction, where the azides, with electron donating and electron withdrawing groups acted as 1,3-dipoles and 1-ethynyl-1-cyclohexanol served as the terminal alkyne. These synthesized triazoles were subjected to enzymatic assay which showed promising activity against α-glucosidase; 1-(2-cyano-4-nitrophenyl)-4-(1-hydroxycyclohexyl)-1H-1,2,3-triazole 3m being the most active members of the library. Molecular docking studies of these triazoles with the homology-modeled α-glucosidase protein were also performed to delineate ligand-protein interactions at molecular level which suggested that Phe157, Arg312 and His279 are the major interacting residues in the biding site of the protein and may have a significant role in the inhibition of enzyme's function.