Synthesis, Characterization Biological/ Photo Electrochemical Assay of Diverse Heterocyclic and Azo Scaffolds and Related Motifs

Abstract

This research pertains to the synthesis, characterization and bio-evaluation of hybrid compounds in which two or more medicinally important nuclei are joined together in a single structural unit. Molecular docking studies were conducted to delineate the binding affinity of the molecules and a kinetic mechanism and mode of enzyme inhibition were proposed. The hybrids include thiazole-based coumarins arylideneamino thiazolyl ethanones, Azo-azomethines, Aza-thiosemicarbazones and sulfonamide-drug conjugates, In addition triazolo [1,2 a] [1,2,4]triazole-1,5-dithones, Thiazoliadinone, 6-aryl-[1,2,4] triazolo [3,4b] [1,3,4] thiadiazoles, pyrazoles, thiazolo [3,2-b]-[a1,2,4]-triazoles, were also prepared . An efficient synthesis of thiazolo-coumarin derivatives; (213-222) was accomplished in three steps from suitable reactants. UV Visible spectra of the compounds were carried out in different solvents DMF, ethanol, methanol, ethyl acetate and acetone and the absorption was observed in the range 338-390 nm. Electrochemical study of thiazoles was conducted in DMF and redox behavior was also examined. Fluorescence carried out in ethanol showed sharp emission in the range 440-505 nm. Another one-pot synthesis of coumarinyl appended thiazoles was achieved by the reaction of 3-bromoacetylcoumarin with separately prepared thiosemicarbazones.The synthesized molecules were investigated for the inhibition activity against human tissuenonspecific alkaline phosphatase and human intestinal alkaline phosphatase. Most of the tested compounds exhibited the selective and potent inhibition profile towards isozyme. However, few derivatives showed inhibition of both the enzymes. Molecular docking studies were conducted to explore the binding interactions and modes of potent compounds. In addition, a novel series of thiazole derivatives i.e. arylidene aminothiazolylethanones (236-243) was synthesized by treating 3-Chloropentane-2, 4dione with urea followed by reaction with suitably substituted benzaldehydes. These derivatives were subjected to biological evaluation as potential inhibitors of cholinesterases i.e. acetylcholinesterase (AChE) and butyrylcholinesterase (BChE).In all synthesized compounds except two compounds i.e. (236) and (241); all compounds were identified as selective inhibitors of AChE. Compound (236) exhibited potent inhibitory values against AChE (IC50±), exhibiting =7 times greater selectivity for AChE over BChE. Kinetics studies were performed to find out the mechanism of inhibition of the respective enzyme. In addition, molecular docking studies of most potent inhibitors were also carried out to know the binding interactions between AChE and BChE, respectively. All compounds were found as potent selective inhibitors of AChE except two compounds which exhibited dual inhibitory activities but these compounds were highly selective toward AChE as compared to BChE.

Additionally naked-eye coloured chemodosimeteric probes (244-249), based on Schiffazo dye conjugates were prepared and characterized. The compounds (244-249), exhibited excellent selectivity and high sensitivity in absorbance toward detection of Fe(III) in alcoholic solutions under neutral pH conditions. The detection limit of the probe was shown to be up to 0.05 ppm. A simple paper test strip system for the rapid monitoring of Fe(III) was developed, indicating their convenient use in environmental samples. Electrochemical analysis of metal-free conjugates and iron chelated probes confirmed the chelation of ligands.

A novel series of 2-(hetero(aryl)methylene) hydrazine-1-carbothioamides including two aryl derivatives were synthesized (250-265) by the reaction of thiosemicarbazide with the aldehyde, and tested for their inhibitory activity against urease. Compound (E)-2-(furan2-ylmethylene) hydrazine-1-carbothioamide (255), possessing a furan ring, was the most potent inhibitor of urease with an IC50 value of 0.58 lM. Molecular modelling was carried out. through docking the designed compounds into the urease binding site to predict whether these derivatives have analogous binding mode to the urease inhibitors.

A single-step methodology was developed to synthesize 3,7-Dialkyltetrahydro-1H,5H[1,2,4]triazolo[1,2-a][1,2,4]triazole- ,5-dithiones in improved yields by acid-catalyzed reaction of thiosemicarbazide and aliphatic aldehydes in anhydrous ethanol at reflux temperature. The products were obtained in good to excellent yields. A plausible mechanism involving two successive intramolecular hetero-cyclizations of thiosemicarbazone has also been proposed. The synthesized compounds were characterized by spectroscopic methods and confirmed by using X-ray crystallography. These C-2 symmetric hexaheteroatomic fused heterocycles are expected to have exceptional applications. Synthesis and enzyme inhibitory kinetics of methyl [2-(arylmethylenehydrazono)-4-oxothiazolidin-5-ylidene] acetates (278-287) as mushroom tyrosinase inhibitors. The compounds were synthesized via cyclocondensation of thiosemicarbazones (278-287) with dimethyl but-2-ynedioate (DMAD) in good yields under solvent-free conditions. The synthesized compounds were evaluated for their potential to inhibit the activity of mushroom tyrosinase. It was unveiled that compounds (286) indicated excellent enzyme inhibitory activity with 3.17 mM while IC50 of standard kojic acid is 15.91 mM. The presence of heterocyclic pyridine ring in compound (286) play important role in enzyme inhibitory activity as rest of the functional groups are common in all prepared compounds. New 3,6-Diaryl-[1,2,4]triazolo[3,4-b] [1,3,4]thiadiazoles (304-318) was achieved by phosphine free, C–H arylative cross-coupling of 6-Aryl-[1,2,4]triazolo[3,4b][1,3,4]thiadiazoles (289-303) with suitably substituted iodoanilines using 1-(2naphthoyl)-3-(4-bromophenyl) thiourea as a ligand. The requisite triazolothiadiazoles (289-303) were obtained by the condensation of 4-Amino-1, 2, 4-triazole- 3-thiol with suitably substituted aromatic acids in the presence of phosphoryl chloride. Another small series of new 3,5-Dimethyl-4-(arylsulfanyl) pyrazoles have been synthesized in good to excellent yields by a grinding-induced, sequential one-pot three-component reaction, of an equimolar mixture of 3-Chloro-2,4-pentanedione, differently substituted thiophenols, and hydrazine hydrate in the presence of piperidine under solvent-free conditions. Aryl pyrazoles are the well-recognized class of heterocyclic compounds found in several commercially available drugs. Owing to their significance in medicinal chemistry, in this current account, we have synthesized a series of suitably substituted aryl pyrazole by employing Suzuki cross-coupling reaction. All compounds were evaluated for inhibition of mushroom tyrosinase enzyme both in vitro and in silico. Compound (333) (IC50 =1.568 ± 0.01µM) showed relatively better potential compared to reference kojic acid (IC50 =16.051 ± 1.27 µM).Ten fused heterocyclic derivatives bearing the 2,6-Di(substituted phenyl)thiazolo[3,2-b]1,2,4-triazoles as central rings were synthesized. In vitro inhibitory activities of synthesized compounds on α-amylase, α-glucosidase and α-burylcholinesterase (αBuChE) were evaluated using purified enzyme assays. Compound (342) demonstrated strong and selective α-amylase inhibitory activity (IC50 = 1.1 mmol/g). The compound (346) exhibited excellent inhibition against α-glucosidase (IC50 = 1.2 mmol/g) when compared with acarbose (IC50 = 4.7 mmol/g) as a positive reference. Compound (348) was found to be most potent derivative against α-BuChE with the IC50 of 1.5 mmol/g which was comparable to the (4.7 mmol/g) positive control (galantamine hydrobromide). 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 evaluated. All the 24 synthesized compounds exhibited excellent potential for urease enzyme. Compound (354) (IC50 = 0.081±0.003 µM), 356 ( IC50 = 0.0022 ±0.0002 µM), 366 ( IC50 = 0.0250 ±0.0007 µM) and 371 ( IC50 = 0.0266±0.0021 µM) were found to be the lead compounds compared to standard (thiourea, IC50= 17.814).