Design, synthesis, characterization and in vitro evaluation of some novel thiol-substituted 1,3,4-oxadiazoles as GlmS inhibitors

The development of novel medications with previously unidentified action mechanisms is required due to the increasing in antibiotic resistance amongst dangerous microbes. The major goal of the research was to develop in silico and in vitro antibacterial methods for designing an active thiol substituted oxadiazole inhibitor targeting gram-negative and gram-positive bacteria's GlmS receptor. 1,3,4-Oxadiazole was proposed as a scaffold, and the possibility of its synthesis was examined. The least amount of free energy in the ligand configurations was chosen. Analyses of the novel molecules' characteristics were done using ADMET studies. There were four distinct reactions used in the synthesis processes. As the first reagent, substituted carboxylic acids were utilized. Synthesized compounds were characterized by spectral studies and minimum inhibitory concentration was evaluated by in vitro antibacterial examinations of synthesized compounds. Ciprofloxacin served as the study's reference drug. Based on in vitro studies and in silico molecular docking, ROS1-4 established strong binding energy, while ROS3 revealed significant antibacterial activity. These findings support the hypothesis that the proposed scaffold significantly inhibits the GlmS receptor protein.

Synthesis, antimicrobial evaluation and in silico studies of the (E)-3-(aryl)-5-styryl-1,2,4-oxadiazoles

In recent years, investigations in the field of oxadiazoles have been intensified due to their numerous therapeutic uses. Oxadiazoles are a class of compounds that exhibit several biological applications, citing antimicrobial, anti-inflammatory, anti-diabetic, anthelmintic, anti-tumor, among others. Encouraged by the biological potential of oxadiazoles, were carried out synthesis, antimicrobial evaluation and in silica studies of five (E)-3-(aryl)-5-styryl-1,2,4-oxadiazoles. In this way, (Z)-aryl-N'-hydroxybenzimidamides and ethyl (E)-cinnamate were synthesized, which were subjected to an O-acylamidoxime reaction after by dehydration using microwave irradiation to form the oxadiazole nucleus. The compounds were characterized by spectroscopic techniques, while in vitro antimicrobial activity was evaluated against S. aureus, E. faecalis, E. coli, P. aeruginosa, and against the fungus C. utilis using the microplate microdilution method. Thus, (Z)-aryl-N'-hydroxybenzimidamides, ethyl (E)-cinnamate, and (E)-3-(aryl)-5-styryl-1,2,4-oxadiazoles were synthesized with yields ranging from moderate to good. The (E)-3-(aryl)-5-styryl-1,2,4-oxadiazoles exhibited a reduced spectrum of action, which were active against the bacterium P. aeruginosa and for the fungus C. utilis.

Synthesis Of Some 2,3-Dihydro-1,3,4-Oxadiazoles And 4,5-Dihydro-1,2,4-Triazoles As Anticancer Agents

Objective: The main objective of this work was to synthesize and evaluate the novel 2,3-dihydro-1,3,4-oxadiazole and 4,5-dihydro-1,2,4-triazole derivatives for cytotoxic activities. Methods: The 2,3-dihydro-1,3,4-oxadiazole derivatives 4a-h were synthesized by cyclization of N'-(substituted-benzylidene) isonicotinohydrazide 3a-e in refluxing acetic anhydride. The 2,3-dihydro-1,3,4-oxadiazole derivatives 4a-h were converted into the corresponding 4,5-dihydro-1,2,4-triazoles 5a-h using ammonia. All the synthesized compounds were identified, depending on the physical and spectral data. Title compounds were assessed for their cytotoxic activity against human cancer cell line (MCF-7) by using Sulforhodamine B (SRB) colorimetric assay. Results: All the synthesized compounds showed characteristic peaks in FTIR, 1HNMR and Mass spectral analysis. The results of the in vitro cytotoxic activity revealed that the compound 4c exhibited equipotent cytotoxic activity with an IC50 value of 8.04 µM when compared with that of standard drug doxorubicin (IC50= 8.02 µM). The reminder compounds have shown good to moderate cytotoxic activities when compared with that of a reference standard. Conclusion: We synthesized a series of title compounds in quantitative yields. Most derivatives showed moderate to good cytotoxic activity.

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.

Development of a novel method for UPLC-QTOF-MS analysis of anti-schis-tosomiasis heterocyclic compounds / 中国血吸虫病防治杂志

Objective To develop an ultra-performance liquid chromatography/quadrupole-time of flight mass spectrometry(UPLC-QTOF-MS)method for the determination of an oxadiazole-2-oxide heterocyclic compound F-2015-14.Methods Mouse plasma and liver homogenate specimens were extracted with ethyl acetate and chromatographed on a Waters CORTECS column(C18,1.6μm,2.1 mm×150 mm)by using a mobile phase of 10％acetonitrile-0.1％formic acid with by a volume fractionation by gradient elution.Then,UPLC-QTOF-MS was performed to determine F-2015-14 in mouse plasma and liver homogenate speci-mens.Results The linearity of F-2015-14 in plasma ranged from 12.5 to 250 μg/mL with a correlation coefficient of 0.990 and a detection limit of 8.8 μg/mL.F-2015-14 in liver homogenates ranged from 12.5 to 250 μg/mL.The linearity was good with a cor-relation coefficient of 0.992 and a limit of detection of 5.6 μg/mL.If the concentration of plasma and liver homogenate specimens was 12.5 μg/mL,the accuracy and the matrix effect were 80％to 120％,and the inter-day and intra-day precision was within 20％.If the concentrations of plasma and liver homogenate specimens were 100 μg/mL and 200 μg/mL,the accuracy and the ma-trix effect were 85％to 115％,and the inter-day and intra-day precision was within 15％.Conclusion The UPLC-QTOF-MS es-tablished in this study has a high sensitivity and good reproducibility for the determination of F-2015-14,which provides bases for the development of novel anti-schistosomiasis drugs.

Synthesis and antifungal activity of the novel azole compounds / 药学实践杂志

Objective To design and synthesize novel triazole antifungal derivatives with 1 ,3 ,4-oxadiazole side chain for the study of antifungal activities. Methods Fourteen title compounds were synthesized via acylation ,aminolysis reaction ,cy-clization ,nucleophilic substitution ,etc. All the compounds were characterized by 1 H NMR ,MS spectra. The in vitro antifun-gal activities were evaluated against six human pathogenic fungi through the micro-broth dilution method. Results The title compounds exhibited strong antifungal activities against all the tested fungi ,especially against Candida albicans. Compounds 10d ,10i , 10l , and 10n were found to be the most effective , with a minimum inhibitory concentration (MIC80 ) of 0.003 9 μg/ml .They are 16-fold more potent than ICZ ( MIC80 0.062 5 μg/ml) and 64-fold more potent than FCZ (MIC80 0.25 μg/ml) .Conclusion The 1 ,3 ,4-oxadiazole side chain could affect the antifungal activities. That could be due to the prop-er incorporation between the 1 ,3 ,4-oxadiazole substituted phenyl ring with the target enzyme.

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.

Design, synthesis and biological evaluation of oxadiazole derivatives as xanthine oxidase inhibitors / 药学学报

Xanthine oxidase (XO) is an important target for the treatment of hyperuricemia and gout. Based on the two known non-purine xanthine oxidase inhibitors, febuxostat and topiroxostat, 14 oxadiazole derivatives have been designed and synthesized. These compounds have been evaluated against XO and five of them exhibited significant inhibitory activities at the concentrations below 10 μmol·L-1.

Synthesis and in vivo Anti-inflammatory and Analgesic activities of Oxadiazoles clubbed with Benzothiazole nucleus.

The aim of the present work is to synthesize and evaluate the anti-inflammatory and analgesic activity of 2-(5-substituted-1,3,4-oxadiazole-2-yl)-1,3-benzathiazole derivatives. In the present investigation, a series of 2-(5-substituted-1,3,4-oxadiazole-2-yl)-1,3-benzathiazole derivatives (3a1-3a9) were synthesized by condensing benzothiazolyl carboxyhydrazide and appropriate aryl acids in the presence of phosphorous oxychloride. Structures of synthesized compounds were established on the basis of IR, 1H NMR, and Mass spectroscopy. All the synthesized compounds were screened for their in-vivo anti-inflammatory and analgesic activities at the dose of 50 mg/kg and 10 mg/kg po. The biological result shows that some compounds were good in their anti-inflammatory and analgesic actions.

Synthesis and in vivo Anti-inflammatory and Analgesic activities of Oxadiazoles clubbed with Benzothiazole nucleus.

The aim of the present work is to synthesize and evaluate the anti-inflammatory and analgesic activity of 2-(5-substituted-1,3,4-oxadiazole-2-yl)-1,3-benzathiazole derivatives. In the present investigation, a series of 2-(5-substituted-1,3,4-oxadiazole-2-yl)-1,3-benzathiazole derivatives (3a1-3a9) were synthesized by condensing benzothiazolyl carboxyhydrazide and appropriate aryl acids in the presence of phosphorous oxychloride. Structures of synthesized compounds were established on the basis of IR, 1H NMR, and Mass spectroscopy. All the synthesized compounds were screened for their in-vivo anti-inflammatory and analgesic activities at the dose of 50 mg/kg and 10 mg/kg po. The biological result shows that some compounds were good in their anti-inflammatory and analgesic actions.

Synthesis and antitumor activity fluoroquinolon-3-yloxadiazole sulfanylacetylhydrazone derivatives / 中国药学杂志

OBJECTIVE: To explore an efficient modification strategy for a bioisotere antibacterial fluoroquinolon-3-yl carboxylic acid group for developing compounds with improved antitumor activity. METHODS: Novel title 2-(fluoroquinolon-3-yl)-oxadiazole-5-sulfanylacetylhydrazone derivatives were designed on the basis the pharmacophore skeleton transition principle, and the in vitro activity the title compounds was evaluated by MTT assay. RESULTS: Fourteen target compounds were synthesized from ofloxacin and exhibited more potent antitumor activity than the parent compound, especially the compounds with a carboxylic group-substitued phenyl ring as a modified group around the bioisostere, which had comparable activity to doxorubicin. CONCLUSION: A hydrazone with electron-withdrawing substituents warrants further development as the modified side-chain for the C-3 bioisostere.

Synthesis and antitumor evaluation of fluoroquinolon C3 s-triazole oxadiazole methylsulfide derivatives of ofloxacin / 中国药学杂志

OBJECTIVE: To explore an efficient heterocyclic bioisostere as the C3 carboxylic group of antibacterial fluoroquinolones for further development of antitumor fluoroquinolones. METHODS: Using the s-triazole ring as an isosteric replacement of the C3 carboxylic group with another different heterocyclic ring, oxadiazole, as a modified group, new bis-(different azole) methylsulfide derivatives, 6-fluoro-7-(4-methyl-piperazin-1-yl)-1, 8-(2, 1-oxpropyl)-5-[5-(aryl-[1, 3, 4]-oxadiazol-2-methylsulfanyl)-4H-[1, 2, 4]-tri-azol-3yl]-quinolin-4(1H)-ones (6a-6j), were designed from ofloxacin (1). The in vitro antitumor activity of 6a-6j against three cancer cell lines was evaluated by MTT assay. RESULTS: Ten title compounds (6a-6j) ere synthesized and their structures were characterized by spectral data. They exhibited significantly higher in vitro antitumor potency than the parent compound ofloxacin. CONCLUSION: The heterocyclic ring, s-triazole, could be used as an efficient isostere of the C-3 carboxylic group for further development of antitumor fluoroquinolone candidates.

Synthesis, Characterization and Screening of Anti-tubercular activity of 2, 5-Disubstituted-1, 3, 4-Oxadiazole.

The synthesis of 2-furyl-5-(substituted)-1,3,4-oxadiazoles was carried out by microwave irradiation of 2-furoic acid and ethanol followed by subsequent hydrazinolysis with hydrazine hydrate. Finally furan-2-acid hydrazide was treated with appropriate carboxylic acid in the presence of phosphorous oxychloride to produce title compounds. The structures of the newly synthesized compounds were established on the basis of spectral analysis such as IR, H1NMR and Mass spectral data. The synthesized compounds were screened for their anti-tubercular activity.

Molecular p prediction, docking studies and synthesis of 5-benzimidazole-1-Yl-methyl –[1,3,4] oxadiazole-2-thiol and their derivatives.

Molecular property is a complex balance of various structural features which determine whether a particular molecule is similar to the known drugs.These properties mainly hydrophobicity, molecular size,flexibility and presence of various pharmacophoric features influence the behavior of molecules in a living organism, including oral bioavailability. This investigation deals with the design and calculation of molecular properties, drug likeness, lipophilicity and solubility parameters of 5-Benzimidazole-1-yl-methyl-[1, 3, 4] oxadiazole-2-thiol and their derivatives using Osiris, mol inspiration ,Mol soft software’s, and ALOPGPS 2.1 program. The compounds followed the Lipinski ‘Rule of five’ for better bioavailability, were synthesized and characterized by IR, NMR, and mass spectral analysis. Furthermore, the binding conformations of these compounds for anti inflammatory activities were determined in silico docking. This is an energy optimization process concerned with the search of the lowest free energy binding mode of a ligand within a protein binding site and estimates the forces involved in the protein-ligand recognition, carried out in Mastro V 2011 in the active site of the cyclooxygenase-2 (COX-2) enzyme.

Synthesis and antitumor activity of fluoroquinolone C-3 heterocycles-oxadiazole derivatives (II) / 中国药学杂志

OBJECTIVE: To discover an efficient route for the conversion of an antibacterial fluoroquinolone to an antitumor one. METHODS: Cyclo-condensation of ofloxacin hydrazide 2 with aromatic carboxylic acids in POCl3 gave the corresponding oxadiazole derivatives 3a-3j, and their antitumor activity was evaluated by MTT assay. RESULTS: Ten title compunds were synthesized and showed potential antitumor activity. CONCLUSION: Heterocycles as isosteric replacement of carboxyl are warrant further development.

Synthesis of fluoroquinolone C-3 heterocycles, bis-oxadiazole methylsulfides and methiodides, and their antitumor activity / 中国药学杂志

OBJECTIVE: To explore an efficient structure modification route to transform antibacterial fluoroquinolones to antitumor ones. METHODS: Compound A[1,3,4] oxadiazol-5-thiol 3 derived from ofloxacin 1 was subjected to nucleophilic substitution with each of chloromethyl-1,3,4-oxadiazoles 4a-4g gave di-oxadiazolyl methylsulfides 5a-5g, followed by a quaternization to form the corresponding methiodides 6a-6g, respectively. The in vitro antitumor activity of the title compounds 5a-5g and 6a-6g against three cancer cell lines was evaluated by MTT method. RESULTS: Fourteen title compunds were synthesized and the structures were characterized by corresponding spectral data. The bioactive assay showed that compounds 5a-5g and 6a-6g exhibited a potential anticancer activity (IC50 < 25 μmol · L-1). The activity of the quaternary ammoniums 6a-6g was higher than that of the corresponding free bases 5a-5g. CONCLUSION: The design and synthesis of antitumor fluoroquinolone based on antibacterial fluoroquinolone C-3 heterocycle are worthy of further study.