Synthesis and biological evaluation of 2,5-disubstituted 1,3,4-oxadiazole derivatives with both COX and LOX inhibitory activity

Dual cyclooxygenase/lipoxygenase (COX/LOX) inhibitors constitute a valuable alternative to classical nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors for the treatment of inflammatory diseases. A series of 3-(5-phenyl/phenylamino-[1,3,4]oxadiazol-2-yl)-chromen-2-one and N-[5-(2-oxo-2H-chromen-3-yl)-[1,3,4]oxadiazol-2-yl]-benzamide derivatives were synthesized and screened for anti-inflammatory, analgesic activity. All the derivatives prepared are active in inhibiting oedema induced by carrageenan. Compound 4e was found more potent with 89% of inhibition followed by compound 4b (86%). Compounds with >70% of anti-inflammatory activity were tested for analgesic, ulcerogenic, and lipid peroxidation profile. Selected compounds were also evaluated for inhibition of COXs (COX-1 and COX-2) and LOXs (LOX-5, LOX-12, and LOX-15). Compound 4e was comparatively selective for COX-2, LOX-5, and LOX-15. Study revealed that these derivatives were more effective than ibuprofen with reduced side effects. It can be suggested that these derivatives could be used to develop more potent and safer NSAIDs.     

Trioxsalen derivatives with lipoxygenase inhibitory activity

Trioxsalen (TRX) is a 4,5′,8-trimethylated psoralen analog presenting interesting biological activities when irradiated with UVA light. A series of TRX derivatives, which where obtained by its chemical modification and incorporation of a variety of unsaturated functions at position 4′ of the psoralen ring-system, were evaluated for their antioxidant activity and their inhibitory activity on soybean lipoxygenase (LOX) and lipid peroxidation. The reducing properties of the compounds were evaluated using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging assay and found to be very low, in the range 0–14%, with the exception of the hydroxamic acid 6 which showed almost identical activity to BHT. TRX derivative 3 significantly inhibited LOX, with IC₅₀ 9.4?μM. With the exception of TRX, all tested analogs inhibited lipid peroxidation in the range of 35–91%. The most potent compound, namely TRX derivative 3, was studied for its anti-inflammatory activity in vivo on rat paw edema induced by carrageenan, and was found to be of almost identical activity to indomethacin. The results of the biological tests are discussed in terms of structural characteristics.     

Synthesis, molecular docking and biological evaluation of 1,3,4-oxadiazole derivatives as potential immunosuppressive agents

A series of novel 1,3,4-oxadiazole derivatives (5a-5s) have been designed, synthesized and evaluated for their immunosuppressive activity. Most of these synthesized compounds were proved to have potent immunosuppressive activity and low toxicity. Among them, compounds (5m-5r) showed the most potent biological activity against lymph node cells. The results of flow cytometry (FCM) and western blotting demonstrated that compound 5q induce cell apoptosis by the inhibition of PI3K/AKT pathway. Molecular docking was performed to position compound 5q into PI3Kγ binding site in order to explore the potential target.     

Synthesis, biological evaluation and molecular docking studies of 1,3,4-oxadiazole derivatives as potential immunosuppressive agents

A series of 1,3,4-oxadiazole derivatives derived from 4-methoxysalicylic acid or 4-methylsalicylic acid (6a-6z) have been first synthesized for their potential immunosuppressive activity. Among them, compound 6z displayed the most potent biological activity against lymph node cells (inhibition=38.76% for lymph node cells and IC(50)=0.31 μM for PI3Kγ). The preliminary mechanism of compound 6z inhibition effects was also detected by flow cytometry (FCM) and the compound exerted immunosuppressive activity via inducing the apoptosis of activated lymph node cells in a dose dependent manner. Docking simulation was performed to position compound 6z into the PI3Kγ structure active site to determine the probable binding model.     

Synthesis and evaluation of 1,3,4-oxadiazole derivatives for development as broad-spectrum antibiotics

The reality and intensity of antibiotic resistance in pathogenic bacteria calls for the rapid development of new antimicrobial drugs. In bacteria, trans-translation is the primary quality control mechanism for rescuing ribosomes arrested during translation. Because trans-translation is absent in eukaryotes but necessary to avoid ribosomal stalling and therefore essential for bacterial survival, it is a promising target either for novel antibiotics or for improving the activities of the protein synthesis inhibitors already in use. Oxadiazole derivatives display strong bactericidal activity against a large number of bacteria, but their effects on trans-translation were recently questioned. In this work, a series of new 1,3,4-oxadiazole derivatives and analogs were synthesized and assessed for their efficiency as antimicrobial agents against a wide range of gram-positive and gram-negative pathogenic strains. Despite the strong antimicrobial activity observed in these molecules, it turns out that they do not target trans-translation in vivo, but they definitely act on other cellular pathways.     

Synthesis,biological evaluation,and molecular docking studies of novel 1,3,4-oxadiazole derivatives possessing benzotriazole moiety as FAK inhibitors with anticancer activity

1,3,4-Oxadiazole derivatives have drawn continuing interest over the years because of their varied biological activities. In order to search for novel anticancer agents, we designed and synthesized a series of new 1,3,4-oxadiazole derivatives containing benzotriazole moiety as potential focal adhesion kinase (FAK) inhibitors. All the synthesized compounds were firstly reported. Among the compounds, compound 4 shows the most potent inhibitory activity against MCF-7 and HT29 cell lines with IC₅₀ values of 5.68 μg/ml and 10.21 μg/ml, respectively. Besides, all the compounds were assayed for FAK inhibitory activity using the TRAP–PCR–ELISA assay. The results showed compound 4 exhibited the most potent FAK inhibitory activity with IC₅₀ values of 1.2 ± 0.3 μM. Docking simulation by positioning compound 4 into the FAK structure active site was performed to explore the possible binding mode. Apoptosis which was analyzed by flow cytometry, demonstrated that compound 4 induced apoptosis against MCF-7 cells. Therefore, compound 4 may be a potential anticancer agent against MCF-7 cancer cell.     

Synthesis,telomerase inhibitory and anticancer activity of new 2-phenyl-4H-chromone derivatives containing 1,3,4-oxadiazole moiety

Based on previous studies, 66 2-phenyl-4H-chromone derivatives containing amide and 1,3,4-oxadiazole moieties were prepared as potential telomerase inhibitors. The results showed most of the title compounds exhibited significantly inhibitory activity on telomerase. Among them, some compounds demonstrated the most potent telomerase inhibitory activity (IC₅₀ < 1 µM), which was significantly superior to the staurosporine (IC₅₀ = 6.41 µM). In addition, clear structure–activity relationships were summarised, indicating that the substitution of the methoxy group and the position, type and number of the substituents on the phenyl ring had significant effects on telomerase activity. Among them, compound A33 showed considerable inhibition against telomerase. Flow cytometric analysis showed that compound A33 could arrest MGC-803 cell cycle at G2/M phase and induce apoptosis in a concentration-dependent way. Meanwhile, Western blotting revealed that this compound could reduce the expression of dyskerin, which is a fragment of telomerase.     

Synthesis and anticancer activity of new [(Indolyl)pyrazolyl]-1,3,4-oxadiazole thioglycosides and acyclic nucleoside analogs

New [(Indolyl)pyrazolyl]-1,3,4-oxadiazole compounds and their derived thioglycosides as well as the corresponding sugar hydrazones were synthesized. The acyclo C-nucleoside analogs of the oxadiazoline base system were also prepared by reaction of acid hydrazides with aldehydo sugars followed by one pot process encompassing acetylation and cyclization of the synthesized hydrazones. The anticancer activity of the newly synthesized compounds was studied against colorectal carcinoma (HCT116), breast adenocarcinoma (MCF7) and prostate cancer (PC3) human tumor cell lines and a number of compounds showed moderate to high activities.     

Synthesis and evaluation of in vitro antioxidant properties of novel 2,5-disubstituted 1,3,4-oxadiazoles

2,5-Disubstituted 1,3,4-oxadiazole compounds are one of the most attractive heterocyclic compounds for researchers due to their biological activities. In the undertaken research, a number of potential 2,5-disubstituted 1,3,4-oxadiazole analogues were synthesized through multi step reaction and characterized by FT-IR, ¹H NMR, mass spectra, and also by elemental analysis. Further benzophenone tagged indole acetohydrazides and 2,5-disubstituted 1,3,4-oxadiazoles were evaluated for antioxidant potential, through different in vitro models such as DPPH, nitric oxide and hydrogen peroxide methods. In the series of compounds some of them had shown good to moderate in vitro antioxidant potential compare to the standard drug ascorbic acid in all the above three methods.     

Synthesis,biological evaluation of benzothiazole derivatives bearing a 1,3,4-oxadiazole moiety as potential anti-oxidant and anti-inflammatory agents

Twenty benzothiazole derivatives bearing a 1,3,4-oxadiazole moiety were synthesized and evaluated for their anti-oxidant and anti-inflammatory activities. Among these compounds, 8h and 8l were appeared to have high radical scavenging efficacies as 0.05 ± 0.02 and 0.07 ± 0.03 mmol/L of IC₅₀ values in ABTS⁺ bioassay, respectively. In anti-inflammatory tests, compound 8h displayed good activity with 57.35% inhibition after intraperitoneal administration, which was more potent than the reference drug (indomethacin). Molecular modeling studies were performed to investigate the binding mode of the representative compound 8h into COX-2 enzyme. In vitro enzyme study implied that compound 8h exerted its anti-inflammatory activity through COX-2 inhibition.     

Synthesis and biological evaluation of some new pyridazinone derivatives

A series of pyridazinone derivatives (19–34) were synthesized with an aim to synthesize safer anti-inflammatory agents. The compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation (LPO) actions. The percentage inhibition in edema at different time intervals indicated that compounds 20, 26, 28 and 34 exhibited good anti-inflammatory potential, comparable with that of ibuprofen (85.77%) within a range of 67.48–77.23%. The results illustrate that 5-(4-fluoro-benzyl)-3-(4-chloro-phenyl)-1,6-dihydro-6-pyridazinone (26) and 5-(4-chloro-benzyl)-3-(4-chloro-phenyl)-1,6-dihydro-6-pyridazinone (20) showed best anti-inflammatory activity. Furthermore, activity is more in case of chloro substitution as compared with methyl-substitution. The compounds synthesized were also evaluated for their ulcerogenic and LPO action and showed superior gastrointestinal safety profile along with reduction in LPO as compared with that of the ibuprofen.     

Synthesis and antifungal activity of novel sulfoxide derivatives containing trimethoxyphenyl substituted 1,3,4-thiadiazole and 1,3,4-oxadiazole moiety

Selective oxidation of sulfides 7 or 8 to sulfoxides 9 or 10 is achieved by mCPBA. The structures of the compounds 9 or 10 are confirmed by elemental analysis, IR, and (1)H NMR. The bioassay results showed that title compound 10a possess high antifungal activities with EC(50) values ranging from 19.91 to 63.97 microg/mL. The mechanism of action of 10a against Sclerotinia sclerotiorum was studied. After treating with compound 10a at 100 microg/mL for 12 h, the mycelial reducing sugar, D-GlcNAc, soluble protein and pyruvate content, chitinase activity showed declining tendency.     

Synthesis of a series of novel 2,5-disubstituted-1,3,4-oxadiazole derivatives as potential antioxidant and antibacterial agents

A series of novel 2,5-disubstituted-1,3,4-oxadiazole derivatives were synthesized and screened for their antimicrobial and antioxidant activities. The assay indicated that compounds 3c, 3d, and 3i exhibited comparable antibacterial and antioxidant activity with first-line drugs. The structure activity relationship and molecular docking study of the synthesized compounds are also reported.     

Synthesis of steroidal diacyl hydrazines and their 1,3,4-oxadiazole derivatives

Homogeneous catalytic hydrazinocarbonylation of some steroid derivatives possessing iodo-alkenyl moiety (17-iodo-androst-16-ene 1, 17-iodo-3-methoxy-estra-1,3,5(10),16-tetraene 2, 17-iodo-4-aza-4-methyl-androst-16-en-3-one 3 and 17-iodo-6beta-hydroxy-3alpha,5alpha-cycloandrost-16-ene 4) were carried out in the presence of a palladium catalyst, a base and acetic or benzoic hydrazide as the nucleophilic reagent. The corresponding N-acetamido-carbamoyl 1a-4a or N-benzamido-carbamoyl derivatives 1b-4b were obtained in high yields. Some of these derivatives served as starting materials for the synthesis of new steroidal 1,3,4-oxadiazole compounds.     

Synthesis and antioxidant activity of novel Mannich base of 1,3,4-oxadiazole derivatives possessing 1,4-benzodioxan

A new series of Mannich base of 1,3,4-oxadiazole derivatives possessing 1,4-benzodioxan (6a–6ae) were synthesized and characterized by ¹H NMR, ESI-MS and elemental analysis. The structure of 6b was further confirmed by single crystal X-ray diffraction. All these novel compounds were screened for their in vitro antioxidant activity employing 2,2′-diphenyl-1-picrylhydrazyl radical (DPPH), 2,2′-azinobis (3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS⁺) and ferric reducing antioxidant power (FRAP) scavenging assays. Due to the combination of 1,4-benzodioxan, 1,3,4-oxadiazoles and substituted phenyl ring, most of them exhibited nice antioxidant activities. In all of these three assays mentioned above, compounds 6f and 6e showed significant radical scavenging ability comparable to the commonly used antioxidants, BHT and Trolox. Seven compounds with representative substituents or activities were selected for further assays in chemical simulation biological systems—inhibition of microsomal lipid peroxidation (LPO) and protection against 2,2′-azobis (2-amidinopropane hydrochloride) (AAPH) induced DNA strand breakage, in which, 6f and 6e were demonstrated to be of the most potent antioxidant activities.     

Synthesis, biological evaluation, and molecular docking studies of 1,3,4-oxadiazole derivatives possessing 1,4-benzodioxan moiety as potential anticancer agents

In present study, a series of new 1,3,4-oxadiazole derivatives containing 1,4-benzodioxan moiety (6a-6s) as potential telomerase inhibitors were synthesized. The bioassay tests demonstrated that compounds 6k, 6l, 6m, 6n and 6s exhibited broad-spectrum antitumor activity with IC(50) concentration range from 7.21 μM to 25.87 μM against the four cancer cell lines, HEPG2, HELA, SW1116 and BGC823. Moreover, all the title compounds were assayed for telomerase inhibition using the TRAP-PCR-ELISA assay. The results showed compound 6k possessed the most potent telomerase activity (IC(50)=1.27 ± 0.05 μM). Docking simulation was performed to position compound 6k into the active site of telomerase (3DU6) to determine the probable binding model.     

Synthesis, biological evaluation, and molecular docking studies of 2-chloropyridine derivatives possessing 1,3,4-oxadiazole moiety as potential antitumor agents

A series of new 2-chloropyridine derivatives possessing 1,3,4-oxadiazole moiety were synthesized. Antiproliferative assay results indicated that compounds 6o and 6u exhibited the most potent activity against gastric cancer cell SGC-7901, which was more potent than the positive control. Especially, compound 6o exhibited significant telomerase inhibitory activity (IC(50)=2.3±0.07μM), which was comparable to the positive control ethidium bromide. Docking simulation was performed to position compound 6o into the active site of telomerase (3DU6) to determine the probable binding model.     

Synthesis and Pin1 inhibitory activity of thiazole derivatives

Pin1 (Protein interacting with NIMA1) is a peptidyl prolyl cis–trans isomerase (PPIase) which specifically catalyze the conformational conversion of the amide bond of pSer/Thr-Pro motifs in its substrate proteins and is a novel promising anticancer target. A series of new thiazole derivatives were designed and synthesized, and their inhibitory activities were measured against human Pin1 using a protease-coupled enzyme assay. Of all the tested compounds, a number of thiazole derivatives bearing an oxalic acid group at 4-position were found to be potent Pin1 inhibitors with IC₅₀ values at low micromolar level. The detailed structure–activity relationships were analyzed and the binding features of compound 10b (IC₅₀ 5.38 μM) was predicted using CDOCKER program. The results of this research would provide informative guidance for further optimizing thiazole derivatives as potent Pin1 inhibitors.     

Synthesis of new 2,5-disubstituted-1,3,4-thiadiazole derivatives and their in vivo anticonvulsant activity

A series of 2,5-disubstituted-1,3,4-thiadiazole derivatives were synthesized by the reaction of 3-(2-cyanopropan-2-yl)-N-(5-(piperazine-1-yl)-1,3,4-thiadiazol-2-yl)benzamide with various sulfonyl chlorides and evaluated for their anticonvulsant activity in MES test. Rotorod method was employed to determine the neurotoxicity. The purity of the compounds is confirmed on the basis of their elemental analysis. The structures of all the new compounds are established on the basis of ¹H NMR and mass spectral data. Out of fifteen compounds, three were found to be potent anticolvunstants. The same compounds showed no neurotoxicity at the maximum dose administered (100 mg/kg).