New 1,3,4-oxadiazole/oxime hybrids: Design,synthesis, anti-inflammatory,COX inhibitory activities and ulcerogenic liability

A series of new 1,3,4-oxadiazole/oxime hybrids were synthesized and designed as potent COX inhibitors. The prepared compounds were evaluated for their anti-inflammatory, antioxidant and ulcerogenic activities. The results indicated that the prepared compounds exhibited remarkable anti-inflammatory activity with (69.60–109.60% of indomethacin activity) after 4 h. In vitro COX inhibitory assay showed that compounds 6d and 7h are potent COX inhibitors with IC₅₀ of (1.10–0.94) and (2.30–5.00) µM on both COX-1 and COX-2 respectively. Compound 7h was found to inhibit both COXs non-competitively with K_i values of 73 µM and 89 µM. Most of the tested compounds showed ulcer-free stomachs compared to indomethacin.     

Novel 1,3,4-oxadiazole/oxime hybrids: Synthesis,docking studies and investigation of anti-inflammatory,ulcerogenic liability and analgesic activities

A novel group of 1,3,4-oxadaiazoles, a group known for their anti-inflammatory activity, is hybridized with nitric oxide (NO) releasing group, oxime, for its gastro-protective action and potential synergistic effect. The synthesized hybrids were evaluated for their anti-inflammatory, analgesic, antioxidant and ulcerogenic activities. Most of the tested compounds showed excellent anti-inflammatory activity with compound 8e being more active than indomethacin. They also showed moderate analgesic activity but no antioxidant one. The ability of the synthesized compounds to inhibit COX-1 and COX-2 is studied and the prepared compounds were able to inhibit both COXs non-selectively with IC₅₀s of 0.75–70.50 μM. Docking studies revealed the mode of interaction of the tested compounds into the empty pocket of the isozymes. All of the synthesized compounds interact with COXs active site with energy scores comparable to that of ibuprofen. All compounds showed a safer profile on the stomach tissue integrity compared to conventional NSAIDs. The designed strategy was applied to ibuprofen to introduce ibuprofen/oxadiazole/NO hybrid. The synthesized ibuprofen hybrid is a promising alternative to ibuprofen having similar anti-inflammatory activity but with safer GIT profile.     

Synthesis and in vitro antiproliferative activities of (5-aryl-1,2,4-oxadiazole-3-yl) methyl d-ribofuranosides

The emergence of multidrug resistance cell lines is one of the major obstacles in the success of cancer chemotherapeutic treatment. Therefore, it remains a big challenge the development of new and effective drugs to defeat cancer. The presence of nitrogen heterocycles in the architectural design of drugs has led to the discovery of new leading compounds. Herein, we report the synthesis, characterization and in vitro antiproliferative activity against six cancer cell lines of d-ribofuranoside derivatives bearing a 1,2,4-oxadiazolic ring, with the aim of developing new active compounds. Most of these derivatives exhibit significant antiproliferative activities in the micromolar range. Noteworthy, the most potent compound of the series showed better selectivity towards the more resistant colon cancer cell line WiDr.     

Synthesis, anti-inflammatory activity and ulcerogenic liability of novel nitric oxide donating/chalcone hybrids

A group of novel nitric oxide (NO) donating chalcone derivatives was prepared by binding various amino chalcones with different NO donating moieties including; nitrate ester, oximes and furoxans. Most of the prepared compounds showed significant anti-inflammatory activity using carrageenan-induced rat paw edema method compared with indomethacin. The prepared compounds exhibited more protection than indomethacin in regard to gastric toxicity. Histopathological investigation confirmed the beneficial effects of the NO releasing compounds in reducing ulcer formation. The incorporation of the NO-donating group into the parent chalcone derivatives caused a moderate increase in the anti-inflammatory activity with a marked decrease in gastric ulcerations compared to their parent chalcone derivatives.     

Synthesis,antiproliferative and antimicrobial activity of new Mannich bases bearing 1,2,4-triazole moiety

Abstract

This study presents the synthesis, antiproliferative and antimicrobial evaluation of a new series of Mannich base derivatives containing 1,2,4-triazole system. New compounds were prepared by the reaction of 4,5-disubstituted 1,2,4-triazole-3-thiones with formaldehyde and various amines. The structures of the prepared compounds were confirmed by means of ¹H NMR, ¹³C NMR and elemental analyses. Twelve compounds were evaluated for their in vitro antiproliferative activities against six chosen cancer cell lines. All synthesized compounds were screened for their in vitro antimicrobial activity by using the agar dilution technique. For 17 potentially active compounds, their antibacterial activity was confirmed on the basis of MIC (minimal inhibitory concentration) by broth microdilution method using the reference Gram-positive and Gram-negative bacterial strains.     

Novel quinoline incorporating 1,2,4-triazole/oxime hybrids: Synthesis,molecular docking,anti-inflammatory,COX inhibition,ulceroginicity and histopathological investigations

A series of novel quinolines incorporating 1,2,4-triazole/oxime hybrids were prepared. They showed remarkable anti-inflammatory activity and exhibited very low incidence of gastric ulceration, compared to indomethacin. Most of the compounds tested showed remarkable inhibition of the COX-1 isozyme, with IC₅₀’s ranging from 0.48 to 28 µM. Compounds 7c and 9g showed high safety profiles with normal stomach tissue integrity. Docking studies supported the observed in vitro inhibitory activity towards the COX enzymes that may explain their promising anti-inflammatory activity relative to indomethacin. Moreover, differences between the COX-1 and COX-2 isozymes in observed energy scores, as well as in the number of interactions with some of the compounds tested, might predict their higher selectivity towards COX-1 rather than COX-2. Compound 9e was found to inhibit both COXs non-competitively with K_i values of 81 µM and 94.6 µM.     

Synthesis and antioxidant activities of some new triheterocyclic compounds containing benzimidazole,thiophene, and 1,2,4-triazole rings

Abstract

Various triheterocyclic compounds containing benzimidazole, thiophene, and 1,2,4-triazole rings (3–6) were synthesized and screened for their antioxidant activities. The structures of the synthesized compounds (2–6) were judged by ¹H NMR, ¹³C NMR, elemental analysis, and LC-MS spectral data. Antioxidant activities of the synthesized compounds (2–6) were determined with CUPric Reducing Antioxidant Capacity (CUPRAC), ABTS (2,2-azinobis(3-ethylbenzothiazoline-6-sulfonic acid)/persulfate, and DPPH (1,1-diphenyl-2-picrylhydrazyl) assays. Most of the compounds showed a significant antioxidant activity and especially, compound 5c showed very good SC₅₀ value for DPPH method and compound 5h exhibited very high scavenging activity to ABTS method.     

Antiproliferative activity and apoptosis inducing effects of nitric oxide donating derivatives of evodiamine

The first series of nitric oxide donating derivatives of evodiamine were designed and prepared. NO releasing ability of all target derivatives was evaluated in BGC-823, Bel-7402 and L-02 cells. The cytotoxicity was evaluated against three human tumor cell lines (Bel-7402, A549 and BGC-823) and normal human liver cells L-02. The nitrate derivatives 11a and 11b only exhibited moderate activity and furoxan-based derivatives 13a–c, 14a and 14b showed promising activity. 13c showed good cytotoxic selectivity between tumor and normal liver cells and was further investigated for its apoptotic properties on human hepatocarcinoma Bel-7402 cells. The molecular mode of action revealed that 13c caused cell-cycle arrest at S phase and induced apoptosis in Bel-7402 cells through mitochondria-related caspase-dependent pathways.     

Novel 1,2,4-triazole derivatives as potential anticancer agents: Design,synthesis, molecular docking and mechanistic studies

A series of novel compounds carrying 1,2,4-triazole scaffold was synthesized and evaluated for their anticancer activity against a panel of cancer cell lines using MTT assay. Compounds 8a, 8b, 8c, 8d, 10b, 10e, and 10 g showed remarkable antiproliferative activity against the tested cell lines. Compounds 8a, 8b, 8c, 8d, 10b, 10e, and 10 g with the least IC₅₀ values in MTT assay were tested against three known anticancer targets including EGFR, BRAF and Tubulin. The results revealed that compounds 8c and 8d showed almost same BRAF inhibitory activity and were discovered to be potent inhibitors of cancer cell proliferation and were also observed to be strong Tubulin inhibitors. Moreover, 8c also showed the best EGFR inhibition with IC₅₀ = 3.6 μM. Finally molecular modeling studies were performed to explore the binding mode of the most active compounds to the target enzymes.     

Design,synthesis, biological activities and DFT calculation of novel 1,2,4-triazole Schiff base derivatives

Series of 1,2,4-triazole Schiff bases (2a-2d, 2f-2h and 3a-3h) have been designed and synthesized. The structure of title compounds was confirmed on the basis of their spectral data and elemental analysis. All the target compounds were screened for their in vitro antifungal activity and antibacterial activity. Two of the tested compounds (2a and 2b) exhibited significant antifungal activity against most fungi, especially compound 2a showed better antifungal activity than triadimefon. Meanwhile, the antibacterial activity assay also indicated compound 2a exhibited excellent antibacterial activities comparable to chloramphenicol. The SAR manifested no substitution at position 5 of the triazole ring caused an increase in activity, and 3-phenoxy phenyl group introduced in 1,2,4-triazole scaffold can enhance the antibacterial activity. The DFT calculation indicated triazole ring, S atom and benzene ring in both of the 2a and 3a make a major contribution to the activity.     

Design,synthesis and apoptosis-related antiproliferative activities of chelidonine derivatives

To get chelidonine derivatives with enhanced antiproliferative activity and selectivity, a series of nitric oxide donating derivatives (10a-f and 11a-j) were designed, synthesized and biologically evaluated. Compared with chelidonine, these compounds exhibited lower IC₅₀ values against human hepatoma cells HepG2, breast cancer cells MCF-7, colon cancer cells HCT-116, as well as leukemia cells K562. Compound 11j displayed the strongest antiproliferative activity with IC₅₀ values of 3.91, 6.90, 4.36 and 1.12 μM against the above four cells, respectively. Nevertheless, it showed an IC₅₀ value >40 μM against human peripheral blood mononuclear cells (PBMCs), which demonstrated high selectivity between normal and cancer blood cells. In further mechanism studies, 11j showed the capability to induce K562 cells apoptosis, S phase cell cycle arrest and mitochondrial membrane potential disorder. Besides, 11j was found to be effective in promoting the expression of proapoptotic protein Bad and suppressing the expression of anti-apoptotic proteins Bcl-xL, catalase, survivin, claspin and clusterin.     

Synthesis and anti-inflammatory activity evaluation of novel triazolyl-isatin hybrids

New isatin-triazole based hybrids have been synthesized and evaluated for their inhibitory activity of TNF-α induced expression of Intercellular Adhesion Molecule-1 (ICAM-1) on the surface of human endothelial cells. Structure-activity relationship (SAR) studies revealed that the presence of the electron-attracting bromo substituent at position-5 of the isatin moiety played an important role in enhancing the anti-inflammatory potential of the synthesized compounds. Z-1-[3-(1H-1,2,4-Triazol-1-yl)propyl]-5-bromo-3-[2-(4-methoxyphenyl)hydrazono]indolin-2-one (19) with an IC₅₀?=?20?μM and 89% ICAM-1 inhibition with MTD at 200?μM was found to be the most potent of all the synthesized derivatives. Introduction of 1,2,4-triazole ring and electron-donating methoxy group on the phenylhydrazone moiety resulted in four-fold increase of the anti-inflammatory activity.     

New Zn complexes based on 1,2,4-triazoles: Synthesis, structure and luminescence

The reaction of 3-(pyridin-2-yl)-5-(2-aminophenyl)-1H-1,2,4-triazole and salicylaldehyde or benzaldehyde leads a new type of 1,2,4-triazole’s derivats. Reactions of these ligands with zinc acetate in ethanol lead to the formation of two new complexes with azomethine or dihydrotriazaindolizine form of ligands. The structures of these complexes were investigated by X-ray analysis. The complexes showed strong green-blue luminescence in solid state.     

Novel pyrimidine-pyridine hybrids: Synthesis,cyclooxygenase inhibition,anti-inflammatory activity and ulcerogenic liability

Some derivatives containing pyrido[2,3-d:6,5d′]dipyrimidine-4,5-diones (9a-f), tetrahydropyrido[2,3-d]pyrimidine-6-carbonitriles (11a-c) and 6-(4-acetylphenyl)-2-thioxo-2,3,5,6,7,8-hexahydro-1H-pyrimido[4,5-d]pyrimidin-4-one (12) were synthesized from 6-amino-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (8). The anti-inflammatory effect of these candidates was determined and the ulcer indices were calculated for active compounds. 7-Amino-5-(3,4,5-trimethoxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrido[2,3-d] pyrimidine-6-carbonitrile (11c) exhibited better edema inhibition than celecoxib. Moreover, compounds 9b, 9d and 11c revealed better COX-2 inhibitory activity in a range (IC₅₀ = 0.25–0.89 µM) than celecoxib (IC₅₀ = 1.11 µM). Regarding ulcerogenic liability, all of the compounds under the study were less ulcerogenic than indomethacin. Molecular docking studies had been carried on active candidates 9d and 11c to explore action mode of these candidates as leads for discovering other anti-inflammatory agents.     

Synthesis,biological activities and SAR studies of new 3-substitutedphenyl-4-substitutedbenzylideneamino-1,2,4-triazole Mannich bases and bis-Mannich bases as ketol-acid reductoisomerase inhibitors

A series of new 3-substitutedphenyl-4-substitutedbenzylideneamino-1,2,4-triazole Mannich bases and bis-Mannich bases were synthesized through Mannich reaction with high yields. Their structures were confirmed by means of IR, ¹H NMR, ¹³C NMR and elemental analysis. The preliminary bioassay indicated that compounds 7g, 7h and 7l exhibited potent in vitro inhibitory activities against ketol-acid reductoisomerase (KARI) with K_i value of (0.38?±?0.25), (6.59?±?2.75) and (8.46?±?3.99)?μmol/L, respectively, and were comparable with IpOHA. They could be new KARI inhibitors for follow-up research. Some of the title compounds also exhibited obvious herbicidal activities against Echinochloa crusgalli and remarkable in vitro fungicidal activities against Physalospora piricola and Rhizoctonia cerealis. The SAR of the compounds were analyzed, in which the molecular docking revealed the binding mode of 7g with the KARI, and the 3D-QSAR results provided useful information for guiding further optimization of this kind of structures to discover new fungicidal agents towards Rhizoctonia cerealis.     

Synthesis and biological evaluations of new nitric oxide-anti-inflammatory drug hybrids

Three novel series of nitroso derivatives (11–15), isoxazolopyrazoles (17a–c) and isoxazolo[3,4-d]pyridazines (18a–c) were prepared from the hydroxyimoyl chloride 10. In vitro COX1?2 inhibition activities were evaluated, both of 17b and 18a proved a promising inhibitory activity with IC₅₀ = 1.12, 0.78 μM in sequent. Carrageenan induced Paw edema, ulcer liability, nitric oxide (NO) release and histopathological study were determined. Most of the prepared compounds showed excellent activities. Reactions of 2-aminopyridine and enaminone with hydroxyimoyl chloride 10 were investigated and proved by 2D NMR. Molecular docking for most active compounds was operated giving a hint for compound–receptor interactions.     

Synthesis and antiproliferative evaluation of 3,5-disubstituted 1,2,4-triazoles containing flurophenyl and trifluoromethanephenyl moieties

An efficient 1,3-dipolar cycloaddition method was performed for the synthesis of a series of monofluoro- and trifluoromethane-3,5-disubstituted 1,2,4-triazoles. This efficient cycloaddition method was to react hydrazonoyl hydrochlorides with a series of aldehydes in the presence of NEt(3) as catalytic basic agent to provide the corresponding product in 28-94%. Their growth inhibitory results against cancer cells indicated that some of the fluorine- and trifluoromethane-containing compounds could effectively inhibit the growth of NCI-H226 and T-cell leukemia (Jurkat) cells. Among the compounds, trifluoromethane-containing 1,2,4-triazoles possessed the five-membered ring groups on the C-5 position of the triazolic ring, including cyclopentyl, 3-furyl, 3-thienyl, and 2-pyrrolyl, possessed the significant inhibitory activity for NCI-H226 cancer cells.     

3-Arylcoumarins: Synthesis and potent anti-inflammatory activity

Chronic inflammation is the persistent and excessive immune response and can lead to a variety of diseases. Aiming to discover new compounds with anti-inflammatory activity, we report herein the synthesis and biological evaluation of 3-arylcoumarins. Thirty five 3-arylcoumarins were prepared through Perkin condensation and further acid-promoted hydrolysis if necessary. In lipopolysaccharide-activated mouse macrophage RAW264.7 cells, 6,8-dichloro-3-(2-methoxyphenyl)coumarin (16) and 6-bromo-8-methoxy-3-(3-methoxyphenyl)coumarin (25) exhibited nitric oxide production inhibitory activity with the IC₅₀ values of 8.5 μM and 6.9 μM, respectively, providing a pharmacological potential as anti-inflammatory agents.     

Synthesis and in vitro evaluation of homoisoflavonoids as potent inhibitors of nitric oxide production in RAW-264.7 cells

Syntheses of natural homoisoflavonoids, (±)-portulacanones A–C (4, 8 and 9), portulacanone D (6), isolated from Portulaca oleracea L. (POL) and their derivatives (3, 5 and 7) have been achieved for the first time along with the synthesis of known derivatives (1 and 2) and their in vitro inhibitory effect against NO production in LPS-induced RAW-264.7 macrophages was evaluated as an indicator of anti-inflammatory activity. All the compounds tested had a concentration-dependent inhibitory effect on NO production by RAW-264.7 macrophages without obvious cytotoxicity. Compounds 3 (97.2% at 10?μM; IC₅₀?=?1.26?µM) followed by 6 (portulacanone D) (92.5% at 10?μM; IC₅₀?=?2.09?µM), 1 (91.4% at 10?μM; IC₅₀?=?1.75?µM) and 7 (83.0% at 10?μM; IC₅₀?=?2.91?µM) were the most potent from the series. This finding was further correlated with the suppressed expression of iNOS induced by LPS. Our promising preliminary results may provide the basis for the assessment of compound 3 as a lead structure for a NO production-targeted anti-inflammatory drug development and also could support the usefulness of POL as a folklore medicinal plant in the treatment of inflammatory diseases.     

Synthesis of new heterocyclic lupeol derivatives as nitric oxide and pro-inflammatory cytokine inhibitors

A series of heterocyclic derivatives including indoles, pyrazines along with oximes and esters were synthesized from lupeol and evaluated for anti-inflammatory activity through inhibition of lipopolysaccharide (LPS) induced nitric oxide (NO) production in RAW 264.7 and J774A.1 cells. All the synthesized molecules of lupeol were found to be more active in inhibiting NO production with an IC₅₀ of 18.4–48.7 μM in both the cell lines when compared to the specific nitric oxide synthase (NOS) inhibitor, L-NAME (IC₅₀ = 69.21 and 73.18 μM on RAW 264.7 and J774A.1 cells, respectively). The halogen substitution at phenyl ring of indole moiety leads to potent inhibition of NO production with half maximal concentration ranging from 18.4 to 41.7 μM. Furthermore, alkyl (11, 12) and p-bromo/iodo (15, 16) substituted compounds at a concentration of 20 μg/mL exhibited mild inhibition (29–42%) of LPS-induced tumor necrosis factor alpha (TNF-α) and weak inhibition (10–22%) towards interleukin 1-beta (IL-1β) production in both the cell lines. All the derivatives were found to be non-cytotoxic when tested at their IC₅₀ (μM). These findings suggest that the derivatives of lupeol could be a lead to potent inhibitors of NO.