Synthesis, characterization and antibacterial activity of 2-[1-(5-chloro-2-methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-5-(substituted-phenyl)-[1,3,4]oxadiazoles

In the present investigation a series of novel 2-[1-(5-chloro-2-methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-5-(substituted-phenyl)-[1,3,4]oxadiazoles (4a–j) were synthesized by cyclization of substituted-benzoic acid N′-[1-(5-chloro-2-methoxy-phenyl)-5-methyl-1H-pyrazole-4-carbonyl]-hydrazide by using phosphorousoxychloride at 120 °C. The chemical structure of the newly synthesized compounds was characterized by analytical and spectral (IR, ¹H NMR, ¹³C NMR and LC–MS) methods. The title compounds were screened for qualitative (zone of inhibition) and quantitative antibacterial activity (MIC) by agar cup plate and microtitration methods, respectively. Among the synthesized compounds in this series compound 2-[1-(5-chloro-2-methoxyphenyl)-5-methyl-1H-pyrazol-4-yl]-5-(4-fluorophenyl)-1,3,4-oxadiazole (4b) was found to exhibit significant antibacterial activity with MICs of 22.4, 29.8, 29.6 and 30.0 μg/mL against Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae, respectively. The other compounds exhibited moderate activity when compared to standard substance Ampicillin.     

Synthesis and docking studies of N-(5-(alkylthio)-1,3,4-oxadiazol-2-yl)methyl)benzamide analogues as potential alkaline phosphatase inhibitors

A series of N-(5-(alkylthio)-1,3,4-oxadiazol-2-yl)methyl)benzamides 6a–i were synthesized as alkaline phosphatase inhibitors. The intermediate 5-substituted 1,3,4-oxadiazole-2-thione 4 was synthesized starting with hippuric acid. Hippuric acid in the first step was converted into corresponding methyl ester 2 which upon reaction with hydrazine hydrate furnished the formation of hydrazide 3 . The hippuric acid hydrazide was then cyclized into 5-substituted 1,3,4-oxadiazole-2-thione 4 . The intermediate 4 was then reacted with alkyl or aryl halides 5a–5i to afford the title compounds N-(5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl)benzamides 6a–i . The bioassay results showed that compounds 6a–i exhibited good to excellent alkaline phosphatase inhibitory activity. The most potent activity was exhibited by the compound 6i having IC₅₀ value 0.420 μM, whereas IC₅₀ value of standard (KH₂PO₄) was 2.80 μM. Molecular docking studies was performed against alkaline phosphatase enzyme (PDBID 1EW2) to check binding affinity of the synthesized compounds 6a–i against target protein. The docking results showed that three compounds 6c , 6e , and 6i have maximum binding interactions with binding energy values of −8 kcal/mol. The compound 6i displayed the interactions of oxadiazole ring nitrogen with amino acid His265 having a binding distance 2.13 Ǻ. It was concluded from our results that synthesized compounds, especially compound 6i may serve as lead structure to design more potent inhibitors of human alkaline phosphatase.     

Design,synthesis, and in vitro antituberculosis activity of benzo[6,7]cyclohepta[1,2‐b]pyridine‐1,3,4‐oxadiazole derivatives

A new antitubercular agents, benzo[6,7]cyclohepta[1,2‐b]pyridine‐1,3,4‐ oxadiazole hybrids ( 6a–o ), have been designed and synthesized involving oxidative cyclization of hydrazones by use of di(acetoxy)iodobenzene, characterized by IR,¹H NMR,¹³C NMR, and HRMS, and further confirmed by X‐ray analysis. All the newly synthesized compounds 4a–o evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC27294). Among the compounds tested, the compounds 4o (MIC: 1.56  μg/ml) and 4l, 4m (MIC: 3.125  μg/ml) are promising lead analogues and have shown lower cytotoxicity.     

A novel orally active water-soluble inhibitor of human glutathione transferase exerts a potent and selective antitumor activity against human melanoma xenografts

We designed and synthesized two novel nitrobenzoxadiazole (NBD) analogues of the anticancer agent 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (NBDHEX). The new compounds, namely MC3165 and MC3181, bear one and two oxygen atoms within the hydroxy-containing alkyl chain at the C4 position of the NBD scaffold, respectively. This insertion did not alter the chemical reactivity with reduced glutathione, while it conferred a remarkable increase in water solubility. MC3181 was more selective than NBDHEX towards the target protein, glutathione transferase P1-1, and highly effective in vitro against a panel of human melanoma cell lines, with IC₅₀ in the submicromolar-low micromolar range. Interestingly, the cellular response to MC3181 was cell-type-specific; the compound triggered a JNK-dependent apoptosis in the BRAF-V600E-mutated A375 cells, while it induced morphological changes together with an increase in melanogenesis in BRAF wild-type SK23-MEL cells.MC3181 exhibited a remarkable therapeutic activity against BRAF-V600E-mutant xenografts, both after intravenous and oral administration. Outstandingly, no treatment-related signs of toxicity were observed both in healthy and tumor-bearing mice after single and repeated administrations.Taken together, these results indicate that MC3181 may represent a potential novel therapeutic opportunity for BRAF-mutated human melanoma, while being safe and water-soluble and thus overcoming all the critical aspects of NBDHEX in vivo.     

2-\[(1-取代苯基-1H-1,2,3-三唑-4-基)甲硫基\]-5-(3,4,5-三甲氧基苯基)-1,3,4-二唑化合物的合成及抗真菌活性

[摘要] 目的：寻找高效抗真菌化合物,探讨2-[(1-取代苯基-1H-1,2,3-三唑-4-基)甲硫基]-5-(3,4,5-三甲氧基苯基)-1,3,4-噁二唑化合物的构效关系。方法：设计合成了20个2-[(1-取代苯基-1H-1,2,3-三唑-4-基)甲硫基]-5-(3,4,5-三甲氧基苯基)-1,3,4-噁二唑化合物,用微量液基稀释法测定化合物对6种临床常见致病真菌:白念珠菌、新生隐球菌、热带念珠菌(Candida tropicalis)、近平滑念珠菌、红色毛癣菌、克鲁氏假丝酵母的体外抑菌活性。结果：体外抗真菌活性测试结果表明,所合成的目标化合物对所测菌株均具有一定的体外抗真菌活性。其中化合物8m, 8o对白色念珠菌的抑制活性约为氟康唑,酮康唑的3倍;化合物8a, 8e, 8k, 8l, 8n 和 8p对白色念珠菌的抑制活性也较氟康唑,酮康唑强。结论：所合成的化合物中,苯环上连有体积较小取代基的化合物抗真菌活性较好。 [关键词] 合成;噁二唑;抗真菌活性     

Synthesis and Biological Evaluation of Fatty Hydrazides of By-products of Oil Processing Industry

Some new 2-alkyl-5-mercapto-1,3,4-Oxadiazoles and 3-alkyl-5-mercapto-1,2,3-4H triazoles were synthesized from hydrazides of acid oil and oil recovered from spent bleaching earth. These newly synthesized compounds were characterized on the basis of elemental analysis and evaluated for biological properties. Certain derivatives exhibited fairly high antibacterial and antifungal activities when compared with streptomycin and immidil used as standard antibacterial and antifungal agents respectively.     

A novel five‐step synthetic route to 1,3,4‐oxadiazole derivatives with potent α‐glucosidase inhibitory potential and their in silico studies

A series of new N‐aryl/aralkyl derivatives of 2‐methyl‐2‐{5‐(4‐chlorophenyl)‐1,3,4‐oxadiazole‐2ylthiol}acetamide were synthesized by successive conversions of 4‐chlorobenzoic acid ( a ) into ethyl 4‐chlorobenzoate ( 1 ), 4‐chlorobenzoylhydrazide ( 2 ) and 5‐(4‐chlorophenyl)‐1,3,4‐oxadiazole‐2‐thiol ( 3 ), respectively. The required array of compounds ( 6a–n ) was obtained by the reaction of 1,3,4‐oxadiazole ( 3 ) with various electrophiles ( 5a–n ) in the presence of DMF (N,N‐dimethylformamide) and sodium hydroxide at room temperature. The structural determination of these compounds was done by infrared, ¹H‐NMR (nuclear magnetic resonance), ¹³C‐NMR, electron ionization mass spectrometry, and high‐resolution electron ionization mass spectrometry analyses. All compounds were evaluated for their α‐glucosidase inhibitory potential. Compounds 6a, 6c–e, 6g , and 6i were found to be promising inhibitors of α‐glucosidase with IC₅₀ values of 81.72 ± 1.18, 52.73 ± 1.16, 62.62 ± 1.15, 56.34 ± 1.17, 86.35 ± 1.17, 52.63 ± 1.16 µM, respectively. Molecular modeling and ADME (absorption, distribution, metabolism, excretion) predictions supported the findings. The current synthesized library of compounds was achieved by utilizing very common raw materials in such a way that the synthesized compounds may prove to be promising drug leads.     

A novel series of 2,5-disubstituted 1,3,4-oxadiazoles: synthesis and SAR study for their anticonvulsant activity

In search for a better anticonvulsant drug and the importance of semicarbazones and 2,5-disubstituted 1,3,4-oxadiazoles as anticonvulsant pharmacophore, a series of novel substituted semicarbazones were designed, synthesized, and evaluated for their anticonvulsant activity. The chemical structures of the synthesized molecules were confirmed by elemental and spectral (IR, (1) H NMR, (13) C NMR and MS) analysis. The anticonvulsant activities of the compounds were investigated using maximal electroshock seizure and subcutaneous pentylenetetrazole (scPTZ) models. Efforts were also made to establish structure-activity relationships among synthesized compounds. The results of the present study validated that the pharmacophore model with four binding sites is essential for anticonvulsant activity.     

A Facile One‐Pot Synthesis of 2‐Arylamino‐5‐Aryloxylalkyl‐1,3,4‐Oxadiazoles and Their Urease Inhibition Studies

A one‐pot method for the synthesis of structural type urease inhibitors, 2‐amino‐1,3,4‐oxadiazoles, was developed. The structures of the compounds were established using spectroanalytical techniques and unambiguously confirmed by single‐crystal X‐ray analysis of compound 3o . The synthesized compounds were tested against jack beans urease, and most of the compounds ( 3c , 3g , 3j , 3k , 3n , 3r – 3v ) were found more active than the standard. The most potent compound ( 3u ) had an IC₅₀ value of 6.03 ± 0.02 μm as compared to the IC₅₀ value of the standard (thiourea; 22.0 ± 1.2 μm ). The prominent urease inhibition activity of these compounds may serve as an important finding in the development of less toxic and more potent antiulcer drugs. The compounds were also investigated against four bacterial strains, and some of the compounds ( 3g and 3r ) were found more potent than the standard drug (ciprofloxacin) against all the tested strains. The MIC value for compound 3g was 0.156 μmol/mL against the tested bacterial strains.     

Synthesis and antiviral evaluation of novel 5-(N-Aryl-aminomethyl-1,3,4-oxadiazol-2-yl)hydrazines and their sugars, 1,2,4-triazoles, tetrazoles and pyrazolyl derivatives

A number of new N-arylaminomethyl-1,3,4-oxadiazole derivatives 2, 3a,b, and 9-12a,b were prepared. Sugar (5-N-arylaminomethyl-1,3,4-oxadiazol-2-yl) hydrazones 4-6a,b were synthesized by the reaction of the hydrazino derivatives 3a,b with the corresponding monosaccharides. The novel acyclo-C-nucleosides 7, 8a,b were prepared by heterocyclization of the sugar hydrazones 4, 5a,b with acetic anhydride. A number of the synthesized compounds were tested for their antiviral activity against herpes simplex virus type-1 (HSV-1) and hepatitis-A virus (HAV, MBBcell culture-adapted strain). The results revealed that the sugar hydrazones 6a,b showed higher antiviral activity compared to the other hydrazones and their acetylated derivatives.