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Considering the diversified pharmacological importance of thiazole and triazole heterocyclic moieties, a unique series of S-aralkylated bi-heterocyclic hybrids, 7a-l, was synthesized in a convergent manner. The structures of newly synthesized compounds were characterized by ¹H-NMR, 13C-NMR, IR, and EI-MS spectral studies. The structure-activity relationship of these compounds was envisaged by analyzing their inhibitory effects against tyrosinase, whereby all these molecules exhibited potent inhibitory potentials relative to the standard used. The Kinetics mechanism was ascertained by Lineweaver-Burk plots, which revealed that 7g inhibited tyrosinase non-competitively by forming an enzyme-inhibitor complex. The inhibition constants Ki calculated from Dixon plots for this compound was 0.0057µM. These bi-heterocyclic molecules also disclosed good binding energy values (kcal/mol) when assessed computationally. So, these molecules can be considered promising medicinal scaffolds for the treatment of skin disorders. [ABSTRACT FROM AUTHOR]

The present study describes the anti- melanogenesis effect of Acemetacin (ACE). Essential protein (melanin) that is vital for the skin for defense from UV rays. In the present research, emerging drug ACE was examined for its melanin inhibition using three different (in vitro, in vivo and computational) methods. ACE showed remarkable potency (IC50 = 0.353 ± 0.003 µM) against tyrosinase in the comparison of standard, kojic acid (IC50 = 16.841 ± 1.161 µM) and ACE exhibited competitive inhibition. In the in vivo study zebrafish embryos were exposed with 5, 10, 15 and 20 µM of ACE and same doses for positive control (Kojic Acid). At 72 h treatment, ACE expressively (P<0.001) reduced the level of pigmentation (62.89%) at a concentration of 20 µM, relative to that of kojic acid (39.64%). The binding profile of ACE was confirmed by molecular docking and the stability of the docked complexes was justified by MD simulation. Based on our results, it was concluded that ACE possessed good therapeutic potential against melanogenesis by targeting the tyrosinase. [ABSTRACT FROM AUTHOR]

A variety of 5‐(2H‐tetrazol‐5‐yl)‐4‐thioxo‐2‐(substituted phenyl)‐4,5‐dihydro‐1,3‐oxazin‐6‐ones (3a–k) have been synthesized from 1,3‐oxazine‐5‐carbonitriles (2a–k). The protocol represents an efficient, facile, and novel route from easily available precursors to unprecedented structures that share 1,3‐oxazine and tetrazole motifs of utmost value. All the synthesized compounds (3a–k) were evaluated for their inhibitory potential against mushroom tyrosinase. Results revealed that all examined 1,3‐oxazine‐tetrazole hybrids exhibited significant tyrosinase inhibitory activity while compound 3d having 2‐bromophenyl moiety was the most potent among the series with IC50 value 0.0371 ± 0.0018 μM as compared to the reference kojic acid (IC50 = 16.832 ± 0.73 μM). Inhibitory kinetics showed that compound 3d behaves as a competitive inhibitor. The molecular docking analysis was performed against target protein to investigate the binding mode. Moreover, compounds 3j and 3k displayed superior DPPH radical scavenging activity than other analogues. 1,3‐oxazine‐tetrazole hybrids (3a–k) had been synthesized and evaluated for tyrosinase inhibitory activity. Results indicated that compound 3d having 2‐bromophenyl moiety was most potent among the series with IC50 value 0.0371 ± 0.0018 μM and acts as a competitive inhibitor. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Drug repositioning approach was used to predict the possible therapeutic effects of FDA approved drugs against AD disease. • The screened drugs showed good binding interaction profiles within active region of AChE. • Pharmacogenomics analysis depicted the possible associations between screened drugs and Alzheimer's genes. • Cinitapride showed a comparable results with standard and can be used as possible therapeutic agent in the treatment of AD. Abstract 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. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Synthesis of multi-functional 2-furoic piperazide derivatives. • Enzyme inhibitory studies against different enzymes. • Computational studies to augment the in vitro results. • Suitable therapeutic agents for type 2 diabetes and Alzheimer's disease. • Mild hemolytic agents toward red blood cell membrane. Abstract The heterocyclic compounds have been extensively reported for their bioactivity potential. The current research work reports the synthesis of some new multi-functional derivatives of 2-furoic piperazide (1 ; 1-(2-furoyl)piperazine). The synthesis was initiated by reacting the starting compound 1 with 3,5-dichloro-2-hydroxybenzenesulfonyl chloride (2) in a basic, polar and protic medium to obtain the parent sulfonamide 3 which was then treated with different electrophiles, 4a–g , in a polar and aprotic medium to acquire the designed molecules, 5a – g. These convergent derivatives were evaluated for their inhibitory potential against α -glucosidase, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Acarbose was used as a reference standard for α -glucosidase inhibition while eserine for AChE and BChE inhibition. Some of the synthesized compounds were identified as promising inhibitors of these three enzymes and their bioactivity potentials were also supported by molecular docking study. The most active compounds among the synthetic analogues might be helpful in drug discovery and development for the treatment of type 2 diabetes and Alzhiemer's diseases. [ABSTRACT FROM AUTHOR]

Herein, we design and synthesized new fluorescein based derivatives by insitu formation of fluorescein ester and further treated with corresponding hydrazide and amine to yield respective compounds i.e. FB1, FB2, FB3 and FB4. The spectral purity and characterization was done by using IR, NMR and Mass spectroscopies. The synthesized derivatives were examined for their photophysical properties by using variety of organic solvents and results were discussed in details. The structural diversity of synthesized compounds motivate us to evaluate these compounds for urease inhibition. The compound FB3 (IC50 = 0.0456 μM) shows 100 fold more active against Jack bean urease than standard drug thiourea (IC50 = 4.7455 μM). Other synthesized compounds showed potent activity. Free radical percentage scavenging assay further supported the capacity of compounds to urease inhibition. While, molecular docking simulations helps to examine the molecular interactions of active compounds FB1, FB2, FB3 and FB4 within the binding site of urease enzyme. [ABSTRACT FROM AUTHOR]

A quinoline functionalized two novel fluorescent Schiff bases, N-(quinolin-2-ylmethylene) anthracen-1-amine (SB1) and 2-(quinolin-2-ylmethyleneamino) benzene thiol (SB2) were synthesized and confirmed by using 1H NMR, IR and GC-MS techniques. The spectroscopic properties were examined by absorption spectroscopy and fluorescence spectroscopy. The absorption and fluorescence spectra of the probes (SB1 and SB2) were measured in a variety of solvents. Both the compounds were tested for urease inhibitory activity. The synthesized compound SB2 proved to be the most effective screening for enzyme inhibitory activity with IC50 = 0.111 μM than SB1 (IC50 = 0.287 μM). Molecular docking studies were performed to delineate the binding affinity and conformational positions of chemical compounds within the active region of the target protein. In-vitro analysis depicts the potency of SB1 in free radical scavenging as compared to the reference drug vitamin C. [ABSTRACT FROM AUTHOR]

Cas scaffolding protein family member 4 and protein tyrosine kinase 2 are signaling proteins, which are involved in neuritic plaques burden, neurofibrillary tangles, and disruption of synaptic connections in Alzheimer's disease. In the current study, a computational approach was employed to explore the active binding sites of Cas scaffolding protein family member 4 and protein tyrosine kinase 2 proteins and their significant role in the activation of downstream signaling pathways. Sequential and structural analyses were performed on Cas scaffolding protein family member 4 and protein tyrosine kinase 2 to identify their core active binding sites. Molecular docking servers were used to predict the common interacting residues in both Cas scaffolding protein family member 4 and protein tyrosine kinase 2 and their involvement in Alzheimer's disease-mediated pathways. Furthermore, the results from molecular dynamic simulation experiment show the stability of targeted proteins. In addition, the generated root mean square deviations and fluctuations, solvent-accessible surface area, and gyration graphs also depict their backbone stability and compactness, respectively. A better understanding of CAS and their interconnected protein signaling cascade may help provide a treatment for Alzheimer's disease. Further, Cas scaffolding protein family member 4 could be used as a novel target for the treatment of Alzheimer's disease by inhibiting the protein tyrosine kinase 2 pathway. [ABSTRACT FROM AUTHOR]

In view of considerable interest in the design and synthesis of new heterocyclic compounds with promising biological activities for medical and biological applications, a series of eight imine derivatives have been synthesized through microwave-assisted Schiff base formation by reacting 2-(4-methoxyphenyl)acetohydrazide (3) and 4-amino-3-(4-methoxybenzyl)-1H-1,2,4-triazole-5(4H)-thione (6) with various substituted aldehydes. Structures of the newly synthesized compounds were characterized by FT-IR, H NMR and C NMR spectral analysis. All the synthesized derivatives were screened for their in vivo anti-inflammatory and in vitro anti-oxidant activities using carrageenan induced rat paw edema test and DPPH free radical scavenging assay, respectively. In addition, molecular docking experiment was also performed to check the actual binding affinity of ligand against target protein. Compounds 4a, 4c, 7a, and 7c screened as potent anti-inflammatory drugs significantly lowered the volume of rat paw edema ( P < 0.05). In case of anti-oxidant assay, compound 7a with ferrocenyl group as substituent R and 3,4-disubstitued 1,2,4-triazole as side coupled group exhibited IC value of 7.2 ± 2.7 μg/mL comparable with that of the reference ascorbic acid (2.61 ± 0.29 μg/mL) and was the most active compound among the series. However, no prominent results were obtained in case of aralkanoic acid hydrazide substituted Schiff base derivatives 4a - 4d. It is believed that the synthesized Schiff base derivatives can be used for the development of potent anti-inflammatory and anti-oxidant drugs with considerable advantages of convenient synthetic strategy possessing high product yield, short reaction time, and convenient handling. The molecular docking results were found in good correlation with experimental IC values. [ABSTRACT FROM AUTHOR]

The present article describes the synthesis, in vitro urease inhibition and in silico molecular docking studies of a novel series of bi-heterocyclic bi-amides. The synthesis of title compounds was initiated by benzoylation, with benzoyl chloride ( 1 ), of the key starter ethyl 2-(2-amino-1,3-thiazol-4-yl)acetate ( 2 ) in weak basic aqueous medium followed by hydrazide formation, 4 , and cyclization with CS 2 to reach the parent bi-heterocyclic nucleophile, N -{4-[(5-sulfanyl-1,3,4-oxadiazol-2-yl)methyl]-1,3-thiazol-2-yl}benzamide ( 5 ). Various electrophiles, 8a–l , were synthesized by a two-step process and these were finally coupled with 5 to yield the targeted bi-heterocyclic bi-amide molecules, 9a–l . The structures of the newly synthesized products were corroborated by IR, 1 H NMR, 13 C NMR, EI-MS and elemental analysis. The in vitro screening of these molecules against urease explored that most of the compounds exhibit potent inhibitory potential against this enzyme. The compound 9j , with IC 50 value of 2.58 ± 0.02 µM, exhibited most promising inhibitory activity among the series, relative to standard thiourea having IC 50 value of 21.11 ± 0.12 µM. In silico studies fully augmented the experimental enzyme inhibition results. Chemo-informatics analysis showed that synthesized compounds ( 9a–l ) mostly obeyed the Lipinski's rule. Molecular docking study suggested that ligand 9j exhibited good binding energy value (−7.10 kcal/mol) and binds within the active region of target protein. So, on the basis of present investigation, it was inferred that 9j may serve as a novel scaffold for designing more potent urease inhibitors. [ABSTRACT FROM AUTHOR]

The present study comprises the synthesis of a new series of sulfonamides derived from 4-methoxyphenethylamine (1). The synthesis was initiated by the reaction of 1 with 4-methylbenzenesulfonyl chloride (2) in aqueous sodium carbonate solution at pH 9 to yield N-(4-methoxyphenethyl)-4-methylbenzensulfonamide (3).This parent molecule 3 was subsequently treated with various alkyl/aralkyl halides, (4a-j), using N,N-dimethylformamide (DMF) as solvent and LiH as activator to produce a series of new N-(4-methoxyphenethyl)-N-(substituted)-4-methylbenzenesulfonamides (5a-j). The structural characterization of these derivatives was carried out by spectroscopic techniques like IR, ¹H-NMR, and 13C-NMR. The elemental analysis data was also coherent with spectral data of these molecules. The inhibitory effects on acetylcholinesterase and DPPH were evaluated and it was observed that N-(4-Methoxyphenethyl)-4-methyl- N-(2-propyl)benzensulfonamide (5c) showed acetylcholinesterase inhibitory activity 0.075 ± 0.001 (IC50 0.075 ± 0.001 µM) comparable to Neostigmine methylsulfate (IC50 2.038 ± 0.039 µM). The docking studies of synthesized ligands 5a-j were also carried out against acetylcholinesterase (PDBID 4PQE) to compare the binding affinities with IC50 values. The kinetic mechanism analyzed by Lineweaver-Burk plots demonstrated that compound (5c) inhibits the acetylcholinesterase competitively to form an enzyme inhibitor complex. The inhibition constants Ki calculated from Dixon plots for compound (5c) is 2.5 µM. It was also found from kinetic analysis that derivative 5c irreversible enzyme inhibitor complex. It is proposed on the basis of our investigation that title compound 5c may serve as lead structure for the design of more potent acetylcholinesterase inhibitors. [ABSTRACT FROM AUTHOR]

Research studies on human tyrosinase inhibitors and exploration for better cytotoxic agents remain an important line in drug discovery and development at the present time. Recently, multiple inhibitors are being used to cure melanogenesis by targeting human tyrosinase. A series of coumarin (C1-C9)-, thymol (T1-T8)- and vanillin (V1-V8)-based derivatives have been theoretically analyzed for their inhibitory effects against human tyrosinase. The crystal structure of human tyrosinase is not available in Protein Data Bank. Therefore, homology modeling approach was used to predict three-dimensional (3D) crystal structure of human tyrosinase. The reliability and efficacy of predicted 3D structure were validated by using Ramachandran plots which indicate that 95.01 % residues are present in favored regions. Moreover, multiple computational approaches such as molecular docking and molecular dynamic (MD) simulation along with various online tools were employed to screen the best inhibitor against melanogenesis. The results revealed that V7 and C9 compounds showed significant binding energy values (−7.79 and −7.40 kcal/mol, respectively) compared with the standard drugs such as kojic acid (−4.21 kcal/mol) and arbutin (−4.62 kcal/mol). Moreover, MD simulation results also justified that V7 showed little fluctuations throughout the simulation period as depicted by the root mean square deviation and root mean square fluctuation graphs. Thus, the present in silico study provides a deeper insight into the structural attributes of V7 compound and its overall molecular interactions against human tyrosinase and gives a hypothetical gateway to use this compound as a potential inhibitor against melanogenesis. [ABSTRACT FROM AUTHOR]