Synthesis, Kinetics and Computational Explorations of 4-Phenylpiperazine Bearing N-(Aryl)-3-substituted-benzamides as Auspicious Tyrosinase Inhibitors.

In the aimed research study, a new series of N-(aryl)-3-[(4-phenyl-1-piperazinyl)methyl]benzamides was synthesized, which was envisaged as tyrosinase inhibitor. The structures of these newly designed molecules were verified by IR, 1H-NMR, 13C-NMR, EI-MS and CHN analysis data. These molecules were screened against tyrosinase and their inhibitory activity explored that these 3-substituted-benzamides exhibit good to excellent potential, comparative to the standard. The Kinetics mechanism was investigated through Lineweaver-Burk plots which depicted that molecules inhibited this enzyme in a competitive mode. Moreover, molecular docking was also performed to determine the binding interaction of all synthesized molecules (ligands) with the active site of tyrosinase enzyme and the results showed that most of the ligands exhibited efficient binding energy values. Therefore, it is anticipated that these molecules might serve as auspicious therapeutic scaffolds for treatment of the tyrosinase associated skin disorders.

Design of potent tyrosinase inhibiting N-arylated-4-yl-benzamides bearing 2-aminothiazole-triazole bi-heterocycles: mechanistic insight through enzyme inhibition, kinetics and computational studies.

By using a convergent methodology, a unique series of N-arylated 4-yl-benzamides containing a bi-heterocyclic thiazole-triazole core was synthesized and the structures of these hybrid molecules, 9a-k, were corroborated through spectral analyses. The in vitro studies of these multi-functional molecules demonstrated their potent mushroom tyrosinase inhibition relative to the standard used. The kinetics mechanism was exposed by lineweaver-burk plots which revealed that, 9c, inhibited mushroom tyrosinase non-competitively by forming an enzyme-inhibitor complex. The inhibition constant Ki calculated from Dixon plots for this compound was 0.016 µM. The computational study was also consistent with the experimental results and these molecules disclosed good results of all scoring functions and interactions, which suggested a good binding to mushroom tyrosinase. So, it was predicted from the inferred results that these molecules might be considered as promising medicinal scaffolds for the diseases associated with the over-expression of this enzyme.

Biological activity of synthesized 5-{1-[(4-chlorophenyl)sulfonyl]piperidin-4-yl}-2-mercapto-1, 3, 4-oxadiazole derivatives demonstrated by in silico and BSA binding studies

We synthesized a series of compounds bearing pharmacologically important 1,3,4-oxadiazole and piperidine moieties. Spectral data analysis by 1H-NMR, 13C-NMR, IR and EI-MS was used to elucidate the structures of the synthesized molecules. Docking studies explained the different types of interaction of the compounds with amino acids, while bovine serum albumin (BSA) binding interactions showed their pharmacological effectiveness. Antibacterial screening of these compounds demonstrated moderate to strong activity against Salmonella typhi and Bacillus subtilis but only weak to moderate activity against the other three bacterial strains tested. Seven compounds were the most active members as acetyl cholinesterase inhibitors. All the compounds presented displayed strong inhibitory activity against urease. Compounds 7l, 7m, 7n, 7o, 7p, 7r, 7u, 7v, 7x and 7v were highly active, with respective IC50 values of 2.14±0.003, 0.63±0.001, 2.17±0.006, 1.13±0.003, 1.21±0.005, 6.28±0.003, 2.39±0.005, 2.15±0.002, 2.26±0.003 and 2.14±0.002 µM, compared to thiourea, used as the reference standard (IC50 = 21.25±0.15 µM). These new urease inhibitors could replace existing drugs after their evaluation in comprehensive in vivo studies.

Synthesis of new 2-{2,3-dihydro-1, 4-benzodioxin-6-yl[(4-methylphenyl) sulfonyl]amino}-N-(un/substituted-phenyl)acetamides as α-glucosidase and acetylcholinesterase inhibitors and their in silico study

The aim of the present research work was to investigate the enzyme inhibitory potential of some new sulfonamides having benzodioxane and acetamide moieties. The synthesis was started by the reaction of N-2,3-dihydrobenzo[1,4]-dioxin-6-amine (1) with 4-methylbenzenesulfonyl chloride (2) in the presence of 10% aqueous Na2CO3 to yield N-(2,3-dihydrobenzo[1,4]-dioxin-6-yl)-4-methylbenzenesulfonamide (3), which was then reacted with 2-bromo-N-(un/substituted-phenyl)acetamides (6a-l) in DMF and lithium hydride as a base to afford various 2-{2,3-dihydro-1,4-benzodioxin-6-yl[(4-methylphenyl)sulfonyl]amino}-N-(un/substituted-phenyl)acetamides (7a-l). All the synthesized compounds were characterized by their IR and 1H-NMR spectral data along with CHN analysis data. The enzyme inhibitory activities of these compounds were tested against a-glucosidase and acetylcholinesterase (AChE). Most of the compounds exhibited substantial inhibitory activity against yeast a-glucosidase and weak against AChE. The in silico molecular docking results were also consistent with in vitro enzyme inhibition data.

Synthesis and in silico study of 2-furyl(4-{4-[(substituted)sulfonyl]benzyl}-1-piperazinyl)methanone derivatives as suitable therapeutic agents

Abstract In the study presented here, a new series of 2-furyl(4-{4-[(substituted)sulfonyl]benzyl}-1-piperazinyl)methanone derivatives was targeted. The synthesis was initiated by the treatment of different secondary amines (1a-h) with 4-bromomethylbenzenesulfonyl chloride (2) to obtain various 1-{[4-(bromomethyl)phenyl]sulfonyl}amines (3a-h). 2-Furyl(1-piperazinyl)methanone (2-furoyl-1-piperazine; 4) was then dissolved in acetonitrile, with the addition of K2CO3, and the mixture was refluxed for activation. This activated molecule was further treated with equi-molar amounts of 3a-h to form targeted 2-furyl(4-{4-[(substituted)sulfonyl]benzyl}-1-piperazinyl)methanone derivatives (5a-h) in the same reaction set up. The structure confirmation of all the synthesized compounds was carried out by EI-MS, IR and 1H-NMR spectral analysis. The compounds showed good enzyme inhibitory activity. Compound 5h showed excellent inhibitory effect against acetyl- and butyrylcholinesterase with respective IC50 values of 2.91±0.001 and 4.35±0.004 µM, compared to eserine, a reference standard with IC50 values of 0.04±0.0001 and 0.85±0.001 µM, respectively, against these enzymes. All synthesized molecules were active against almost all Gram-positive and Gram-negative bacterial strains tested. The cytotoxicity of the molecules was also checked to determine their utility as possible therapeutic agents.

Synthesis, spectral analysis and pharmacological study of N'- substituted-2-(5-((2,4-dimethylphenoxy)methyl)-1,3,4-oxadiazol-2-ylthio)acetohydrazides

ABSTRACT A series of molecules bearing multiple functional groups were synthesized to study their antibiotic effect against Gram-positive and Gram-negative bacteria and lipoxygenase activity as well. 2,4-Dimethylcarbolic acid (1) was refluxed with ethyl 2-bromoacetate to synthesize ethyl 2-(2,4-dimethylphenoxy)acetate (2). Compound 2 was converted to the corresponding hydrazide 3, again on refluxing with hydrazine. The compound 5-((2,4-dimethylphenoxy)methyl)-1,3,4-oxadiazol-2-thiol (4) was synthesized by the reaction of 3 and CS2 in the presence of KOH. Compound 4 was further converted to the corresponding ester 5 and then 2-(5-((2,4-dimethylphenoxy)methyl)-1,3,4-oxadiazol-2-ylthio)acetohydrazide (6). The final molecules N'-substituted-2-(5-((2,4-dimethylphenoxy)methyl)-1,3,4-oxadiazol-2-ylthio)acetohydrazide, 8a-m, bearing ether, 1,3,4-oxadiazole, thioether, hydrazone and azomethine functional groups were synthesized by stirring the aryl carboxaldehydes 7a-m with 6 in methanol at room temperature. The depicted structures of all synthesized molecules were corroborated by IR, 1H-NMR and EIMS spectral data analysis. 8m and 8i showed substantial antibacterial activity and lipoxygenase inhibitory activity, respectively.

Synthesis of some novel enzyme inhibitors and antibacterial agents derived from 5-(1-(4-tosyl)piperidin-4-yl)-1, 3, 4-oxadiazol-2-thiol

ABSTRACT Keeping in mind the pharmacological importance of the 1,3,4-oxadiazole moiety, a series of new S-substituted derivatives, 5a-h, of 5-(1-(4-tosyl)piperidin-4-yl)-1,3,4-oxadiazol-2-thiol (3) were synthesized. The reaction of p-toluenesulfonyl chloride (a) and ethyl isonipecotate (b) produced ethyl 1-(4-tosyl)piperidin-4-carboxylate (1) which was further transformed into 1-(4-tosyl)piperidin-4-carbohydrazide (2) by hydrazine hydrate in methanol. Compound 2 was refluxed with CS2 in the presence of KOH to synthesize 5-(1-(4-tosyl)piperidin-4-yl)-1,3,4-oxadiazol-2-thiol (3). The desired compounds, 5a-h, were synthesized by stirring 3 with aralkyl halides, 4a-h, in DMF using NaH as an activator. The structures of synthesized compounds were elucidated by 1H-NMR, IR and EI-MS spectral studies. These compounds were further evaluated for enzyme inhibitory activity against lipoxygenase and alpha-glucosidase, along with antibacterial activity against Gram-negative and Gram-positive bacteria.

RESUMO Tendo em vista a importância farmacológica da porção 1,3,4-oxadiazol, sintetizou-se uma série de novos derivados S-substituídos, 5a-h, de 5-(1-(4-tosi)piperidin-4-il)-1,3,4-oxadiazol-2-tiol (3). A reação do cloreto de p-toluenossulfonila (a), com isonipecotato de (b) etila forneceu 1-(4-tosil)piperidin-4-carboxilato de metila (1), que foi, em seguida, transformado em 1-(4-tosil)piperidin-4-carbo-hidrazida (2) por reação com hidrato de hidrazina em metanol. O composto 2 foi submetido a refluxo com CS2 na presença de KOH para se obter 5-(1-(4-tosil)piperidin-4-il)-1,3,4-oxadiazol-2-tiol (3). Os compostos desejados, 5a-h, foram obtidos por agitação de 3 com haletos de aralquila, 4a-h, em DMF, na presença de NaH. As estruturas dos compostos sintetizados foram elucidadas através de análise dos espectros de 1H-MNR, IR e EI-MS. Estes compostos foram, ainda, avaliados quanto à inibição das enzimas lipoxigenase e alfa-glucosidase, juntamente com a atividade antibacteriana contra bactérias Gram positivas e Gram negativas.

Convergent synthesis of new N -substituted 2-{[5-(1H -indol-3-ylmethyl)-1, 3, 4-oxadiazol-2-yl]sulfanyl}acetamides as suitable therapeutic agents

abstract A series of N-substituted 2-{[5-(1H-indol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]sulfanyl}acetamides (8a-w) was synthesized in three steps. The first step involved the sequential conversion of 2-(1H-indol-3-yl)acetic acid (1) to ester (2) followed by hydrazide (3) formation and finally cyclization in the presence of CS2 and alcoholic KOH yielded 5-(1H-indole-3-yl-methyl)-1,3,4-oxadiazole-2-thiol (4). In the second step, aryl/aralkyl amines (5a-w) were reacted with 2-bromoacetyl bromide (6) in basic medium to yield 2-bromo-N-substituted acetamides (7a-w). In the third step, these electrophiles (7a-w) were reacted with 4 to afford the target compounds (8a-w). Structural elucidation of all the synthesized derivatives was done by 1H-NMR, IR and EI-MS spectral techniques. Moreover, they were screened for antibacterial and hemolytic activity. Enzyme inhibition activity was well supported by molecular docking results, for example, compound 8q exhibited better inhibitory potential against α-glucosidase, while 8g and 8b exhibited comparatively better inhibition against butyrylcholinesterase and lipoxygenase, respectively. Similarly, compounds 8b and 8c showed very good antibacterial activity against Salmonella typhi, which was very close to that of ciprofloxacin, a standard antibiotic used in this study. 8c and 8l also showed very good antibacterial activity against Staphylococcus aureus as well. Almost all compounds showed very slight hemolytic activity, where 8p exhibited the least. Therefore, the molecules synthesized may have utility as suitable therapeutic agents.

resumo Uma série de acetamidas 2-{[5-(1H-indol-3-ilmetil)-1,3,4-oxadiazol-2-il]sulfanila} N-substituídas (8a-w) foi sintetizada em três fases. A primeira etapa envolveu a conversão sequencial de ácido 2-(1H-indol-3-il)acético (1) a éster (2), seguido por hidrazida (3) e, finalmente, a e ciclização na presença de CS2 e KOH alcoólico produziu 5-(1H-indol-3-il- metil)-1,3,4-oxadiazole-2-tiol (4). Na segunda etapa, aminas arílicas/aralquílicas(5a-w) reagiram com brometo de 2-bromoacetila (6​​), em meio básico, para se obter acetamidas 2-bromo-N-substituídas (7a-w). Na terceira etapa, estes eletrófilos (7a- w) reagiram com 4, para se obter os compostos alvo (8a-w). A elucidação estrutural de todos os derivados sintetizados foi realizada por 1H-NMR, IR e técnicas de espectrometria de EI-MS. Além disso, eles foram submetidos a triagem de atividade antibacteriana e hemolítica. Análise da inibição enzimática foi bem apoiada pelos resultados de docking molecular. Por exemplo, o composto 8q exibiu melhor potencial inibitório contra α-glicosidase, e os compostos 8g e 8b exibiram, comparativamente, melhor inibição contra butirilcolinesterase (BChE) elipoxigenase (LOX), respectivamente. Do mesmo modo os compostos 8b e 8c mostraram excelente potencial antibacteriano contra SalmonellaTyphi, semelhante ao do ciprofloxacino, antibiótico padrão usado neste estudo. Os compostos 8c e 8l também mostraram excelente potencial antibacteriano contra Staphylococcus aureus . Quase todos os compostos mostraram pequena atividade hemolítica, sendo que o composto 8p apresentou menor atividade. Assim, as moléculas sintetizadas podem ter a sua utilidade como agentes terapêuticos adequados.

2-Phenitidine derivatives as suitable inhibitors of butyrylcholinesterase

This manuscript reports the synthesis of a series of N-substituted derivatives of 2-phenitidine. First, the reaction of 2-phenitidine (1) with benzene sulfonyl chloride (2) yielded N-(2-ethoxyphenyl) benzenesulfonamide (3), which further on treatment with sodium hydride and alkyl halides (4a-g) furnished into new sulfonamides (5a-g). Second, the phenitidine reacted with benzoyl chloride (6) and acetyl chloride (8) to yield the reported N-benzoyl phenitidine (7) and N-acetyl phenitidine (9), respectively. These derivatives were characterized by infrared spectroscopy, ¹H-NMR, and EI-MS, and then screened against acetylcholinesterase, butylcholinesterase, and lipoxygenase enzyme, and were found to be potent inhibitors of butyrylcholinesterase alone.

Este trabalho apresenta a síntese de uma série de derivados da 2-fenetidina N-substituídos. Primeiro, a reação da 2-fenetidina (1) com cloreto de benzenossulfonila (2) conduziu à N-(2-etoxifenil)benzenossulfonamida (3) que, após tratamento com hidreto de sódio e haletos de alquila (4a-g), originou novas sulfonamidas (5a-g). Em segundo lugar, a reação da fenetidina com cloreto de benzoíla (6) e cloreto de acetila (8) conduziu, respectivamente, à N-benzoilfenetidina (7) e N-acetilfenetidina (9). A caracterização destes derivados fez-se por IV, ¹H-RMN e EM-IE. Procedeu-se à avaliação da atividade inibidora destes compostos em relação às enzimas acetilcolinesterase, butirilcolinesterase e lipoxigenase. No entanto, apenas revelaram atividade inibidora da butirilcolinesterase.