Resveratrol-based cinnamic ester hybrids: synthesis,characterization, and anti-inflammatory activity

Twenty-three novel resveratrol-based cinnamic ester hybrids were designed and synthesized. All the compounds were evaluated for their anti-inflammatory activity using RAW264.7 cells. Among them, compound D15 was found to be the most potent one in inhibiting NO production in LPS-stimulated RAW264.7 cells. The further study indicated that compound D15 could suppress expression of proteins iNOS, COX-2, p-p65, and p-IκB LPS-induced. Immunofluorescence further revealed compound D15 could reduce activation p65 in nuclei. All the results indicated that the anti-inflammatory activity of title compound may partly due to its inhibitory effect on the NF-κB signaling pathway.     

Synthesis,biological evaluation,and molecular modelling of new naphthalene-chalcone derivatives as potential anticancer agents on MCF-7 breast cancer cells by targeting tubulin colchicine binding site

Abstract

A series of naphthalene-chalcone derivatives (3a–3t) were prepared and evaluated as tubulin polymerisation inhibitor for the treatment of breast cancer. All compounds were evaluated for their antiproliferative activity against MCF-7 cell line. The most of compounds displayed potent antiproliferative activity. Among them, compound 3a displayed the most potent antiproliferative activity with an IC₅₀ value of 1.42?±?0.15?µM, as compared to cisplatin (IC₅₀?=?15.24?±?1.27?µM). Additionally, the promising compound 3a demonstrated relatively lower cytotoxicity on normal cell line (HEK293) compared to tumour cell line. Furthermore, compound 3a was found to induce significant cell cycle arrest at the G₂/M phase and cell apoptosis. Compound 3a displayed potent tubulin polymerisation inhibitory activity with an IC₅₀ value of 8.4?µM, which was slightly more active than the reference compound colchicine (IC₅₀?=?10.6?µM). Molecular docking analysis suggested that 3a interact and bind at the colchicine binding site of the tubulin.     

Synthesis,cyclooxygenase inhibition and anti-inflammatory evaluation of new 1,3,5-triaryl-4,5-dihydro-1H-pyrazole derivatives possessing methanesulphonyl pharmacophore

A new series of 1,3,5-triaryl-4,5-dihydro-1H-pyrazole derivatives 13a–p were synthesized via aldol condensation of 3/4-nitroacetophenones with appropriately substituted aldehydes followed by cyclization of the formed chalcones with 4-methanesulfonylphenylhydrazine hydrochloride. All the synthesized compounds were evaluated for their cyclooxygenase (COX) inhibition, anti-inflammatory activity and ulcerogenic liability. All compounds were more potent inhibitors for COX-2 than COX-1. While most compounds showed good anti-inflammatory activity, compounds 13d, 13f, 13k and 13o were the most potent derivatives (ED₅₀?=?66.5, 73.4, 79.8 and 70.5?μmol/kg, respectively) in comparison with celecoxib (ED₅₀?=?68.1?μmol/kg). Compounds 13d, 13f, 13k and 13o (ulcer index?=?3.89, 4.86, 4.96 and 3.92, respectively) were 4–6 folds less ulcerogenic than aspirin (ulcer index?=?22.75) and showed approximately ulceration effect similar to celecoxib (ulcer index?=?3.35). In addition, molecular docking studies were performed for compounds 13d, 13f, 13k and 13o inside COX-2 active site which showed acceptable binding interactions (affinity in kcal/mol ?2.1774, ?6.9498) in comparison with celecoxib (affinity in kcal/mol ?6.5330).     

Novel tetrazole and cyanamide derivatives as inhibitors of cyclooxygenase-2 enzyme: design,synthesis, anti-inflammatory evaluation,ulcerogenic liability and docking study

Nineteen new compounds containing tetrazole and/or cyanamide moiety have been designed and synthesised. Their structures were confirmed using spectroscopic methods and elemental analyses. Anti-inflammatory activity for all the synthesised compounds was evaluated in vivo. The most active compounds 4c, 5a, 5d–f, 8a and b and 9a and b were further investigated for their ulcerogenic liability and analgesic activity. Pyrazoline derivatives 9b and 8b bearing trimethoxyphenyl part and SO₂NH₂ or SO₂Me pharmacophore showed equal or nearly the same ulcerogenic liability (UI: 0.5, 0.75, respectively), to celecoxib (UI: 0.50). Most of tested compounds showed potent central and/or peripheral analgesic activities. Histopathological investigations were done to evaluate test compounds effect on rat's gastric tissue. The obtained results were in consistent with the in vitro data on COX evaluation. Docking study was also done for all the target compounds inside COX-2-active site.     

Synthesis and molecular docking studies of some 4-phthalimidobenzenesulfonamide derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors

A series of 4-phthalimidobenzenesulfonamide derivatives were designed, synthesized and evaluated for the inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Structures of the title compounds were confirmed by spectral and elemental analyses. The cholinesterase (ChE) inhibitory activity studies were carried out using Ellman’s colorimetric method. The biological activity results revealed that all of the title compounds (except for compound 8) displayed high selectivity against AChE. Among the tested compounds, compound 7 was found to be the most potent against AChE (IC₅₀=?1.35?±?0.08?μM), while compound 3 exhibited the highest inhibition against BuChE (IC₅₀=?13.41?±?0.62?μM). Molecular docking studies of the most active compound 7 in AChE showed that this compound can interact with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE.     

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.     

Imidazolylchromanones containing alkyl side chain as lanosterol 14α-demethylase inhibitors: synthesis,antifungal activity and docking study

Abstract

Previously, 2-alkylchromans have been introduced as non-azole inhibitors of 14α-demethylase. Accordingly, we incorporated imidazole ring on the 3-position of 2-alkylchromanones to design new inhibitors of 14α-demethylase and potential antifungal agents. Thus, a series of 2-alkyl-3-imidazolylchromanones were synthesized starting from 2-hydroxyphenacyl bromide. The trans-configuration of compounds was confirmed by NMR-spectroscopy. The antifungal activity of title compounds were evaluated against different fungi in comparison with fluconazole and miconazole. trans-2-(1-Pentyl)-3-imidazolylchroman-4-one (4d) showed the most potent activity against yeasts comparable to fluconazole. The experimental data based on ¹H NMR spectroscopy revealed that 2-alkyl side chain and 3-imidazolyl moiety in compound 4d exist predominantly in the di-equatorial conformation. While docking study with 14α-demethylase demonstrated that the di-axial form of compound 4d can be considered as active conformation.     

A facile solid-state synthesis and in vitro antimicrobial activities of some 2,6-diarylpiperidin/tetrahydrothiopyran and tetrahydropyran-4-one oximes

Some 2,6-diarylpiperidin/tetrahydrothiopyran/tetrahydropyran-4-one oximes were synthesized in dry media under microwave irradiation and were evaluated for their in vitro antibacterial activity against clinically isolated bacterial strains i.e. S.aureus, β-H.Streptococcus, E.coli, P.aeruginosa, S.typhii and in vitro antifungal activities against fungal strains i.e. C.albicans, Rhizopus, A.niger and A.flavus. Structure-activity relationships for the synthesized compounds showed that compounds 12 and 15 exerted excellent antibacterial activity against all the tested bacterial strains except 15 against S.aureus and β-H.streptococcus. Against C.albicans and A.flavus, compound 15 exerted potent antifungal activities while against Rhizopus, compound 16 showed promising activity.     

Synthesis of new pyridothienopyrimidinone and pyridothienotriazolopyrimidine derivatives as pim-1 inhibitors

Three series of 2-arylpyridothieno[3,2-d]pyrimidin-4-ones 3a–j, pyridothienotriazolopyrimidines 6–8 and 4-imino-pyridothieno[3,2-d]pyrimidines 9a,b were prepared to improve the pim-1 inhibitory activity of the previously reported 2-arylpyridothieno[3,2-d]pyrimidin-4-ones. All the test compounds showed highly potent pim-1 inhibition with IC₅₀ in the range of 0.06–1.76?µM. No significant difference was detected between the pim-1 inhibitory activity of the 4-pyrimidinone and the 4-imino (=NH) or the cyclised triazolopyrimidine derivatives. The most active compounds were tested for their cytotoxic activity on MCF7 and HCT116 and showed potent activity on both the cell lines.     

Synthesis and anticonvulsant activity evaluation of 6-substituted-[1,2,4]triazolo[3,4-a](tetrazolo[5,1-a])phthalazine derivatives

With the aim of finding new anticonvulsant drugs, new 6-substituted-[1,2,4]triazolo[3,4-a] (tetrazolo[5,1-a]) phthalazine derivatives (1–34) have been designed and synthesized. All the compounds were evaluated for their anticonvulsant activities using the maximal electroshock test (MES). Most of the synthesized compounds exhibited potent anticonvulsant activities in the MES. The most promising compound 14 showed significant anticonvulsant activity in MES test with ED₅₀ value of 9.3 mg/kg. It displayed a wide margin of safety with protective index much higher than the standard drug Carbamazepine. And the potency of compound 14 against seizures induced by Pentylenetetrazole, Isoniazid, Thiosemicarbazide and 3-Mercaptopropionic acid in the chemical-induced seizure tests suggested that compound 14 displayed wide spectrum of activity in several models.     

Synthesis and antileishmanial activity of novel pyridinium-hydrazone derivatives

A series of substituted phenylethylidenehydrazinylpyridinium derivatives bearing methyl, ethyl, propyl, and propylphenyl groups on the pyridinium nitrogen were synthesized and evaluated for in vitro antileishmanial activity against Leishmania tropica by using the microdilution method. Among the tested compounds, 3d, 5c, 3b, and 3c were found to be the most active derivatives against the promastigotes of L. tropica (IC₅₀ values are 6.90, 9.92, 11.69 and 12.03 µM, respectively) and to be more active than reference drug meglumine antimonaite (glucantime) (IC₅₀ value: 20.49 µM). The derivatives investigated in this study may have the potential to be lead compound against leishmanial infection.     

Anti-ulcer and anti-oxidant activity of Pepticare, a herbomineral formulation

Pepticare, a herbomineral formulation of the Ayurveda medicine consisting of the herbal drugs: Glycyrrhiza glabra, Emblica officinalis and Tinospora cordifolia, was tested for its anti-ulcer and anti-oxidant activity in rats. Effects of various doses (125, 250, 500 and 1000 mg/kg, p.o.) of Pepticare were studied on gastric secretion and gastric ulcers in pylorus-ligation and on ethanol-induced gastric mucosal injury in rats. The reduction in ulcer index in both the models along with the reduction in volume and total acidity, and an increase in the pH of gastric fluid in pylorus-ligated rats proved the anti-ulcer activity of Pepticare. It was also found that Pepticare was more potent than G. glabra alone in protecting against pylorus-ligation and ethanol-induced ulcers. The increase in the levels of superoxide dismutase, catalase, reduced glutathione and membrane bound enzymes like Ca²⁺ATPase, Mg²⁺ATPase and Na⁺K⁺ATPase and decrease in lipid peroxidation in both the models proved the anti-oxidant activity of the formulation. Thus it can be concluded that Pepticare possesses anti-ulcer activity, which can be attributed to its anti-oxidant mechanism of action.     

Kukoamine A analogs with lipoxygenase inhibitory activity

Kukoamine A (KukA) is a spermine (SPM) conjugate with dihydrocaffeic acid (DHCA), with interesting biological activities. The four possible regioisomers of KukA, as well as a series of KukA analogs incorporating changes in either the SPM or the DHCA structural units, 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 in the range 5–97.5%. KukA significantly inhibits LOX with IC₅₀ 9.5?μM. All tested analogs inhibited lipid peroxidation in the range of 11–100%. The most potent compounds KukA and its analog 3, in which the DHCA units had been replaced by O,O9-dimethylcaffeic acid units, were studied for their anti-inflammatory activity in vivo on rat paw edema induced by carrageenan and found to be of comparable activity to indomethacin. The results of the biological tests are discussed in terms of structural characteristics.     

A convenient ‘one-pot’ synthesis and in vitro microbiological evaluation of novel 2,7-diaryl-[1,4]-diazepan-5-ones

A convenient method for the ‘one-pot’ synthesis of novel target molecule 2,7-diaryl-[1,4]-diazepan-5-ones from the respective 2,6-diaryl-piperidin-4-ones was catalyzed by NaHSO₄.Al₂O₃ heterogeneous catalyst in dry media under microwave irradiation in solvent-free conditions. Moreover, the catalyst could be recovered and re-used up to 4 times after washing with ethyl acetate. They were evaluated for potential antibacterial activity against Staphylococcus aureus, β-Haemolytic streptococcus, Vibreo cholerae, Salmonella typhii, Escherichia coli, Klebsiella pneumonia, Pseudomonas and antifungal activity against Aspergillus flavus, Aspergillus fumigatus, Mucor, Candida albicans and Rhizopus. Structure-Activity Relationship (SAR) led to the conclusion that, of all the compounds 25–32 tested, compound 30 exerted strong in vitro antibacterial activity against S. aureus, S. typhii, and Pseudomonas and all the compounds 25–32 were less active against E. coli, whereas all the compounds 25–32 displayed potent in vitro antifungal activity against all the fungal strains used, except compound 30, which was more effectual against Mucor.     

Synthesis and Antitumor Evaluation in Vitro of NO‐Donating Ursolic Acid‐Benzylidene Derivatives

Antitumor activity of triterpenoid and its derivatives has attracted great attention recently. Our previous efforts led to the discovery of a series of NO‐donor betulin derivatives with potent antitumor activity. Herein, we prepared eight compounds derived from ursolic acid (UA). All the compounds were evaluated for their in vitro cytotoxicity against four human cancer cell lines (HepG‐2, MCF‐7, HT‐29 and A549). Among the compounds tested, compound 4a was found to be most active against HT‐29 (IC₅₀=4.28 μm ). Further biological assays demonstrated that compound 4a could induce cell cycle arrest at G1 phase and apoptosis in a dose‐dependent manner. In addition, compound 4a was found to upregulate pro‐apoptotic Bax, p53 and downregulate anti‐apoptotic Bcl‐2. All these results suggested that compound 4a is a potential candidate drug for the therapy of colon cancer.     

Design,green synthesis and pharmacological evaluation of novel 5,6-diaryl-1,2,4-triazines bearing 3-morpholinoethylamine moiety as potential antithrombotic agents*

The aim of this research work was to investigate a series of novel 5,6-diaryl-1,2,4-triazines (3a–3q) containing 3-morpholinoethylamine side chain, and to address their antiplatelet activity by in vitro, ex vivo and in vivo methods. All compounds were synthesized by environment benign route and their structures were unambiguously confirmed by spectral data. Compounds (3l) and (3m) were confirmed by their single crystal X-ray structures. Out of all the synthesized compounds, 10 were found to be more potent in vitro than aspirin; six of them were found to be prominent in ex vivo assays and one compound (3d) was found to have the most promising antithrombotic profile in vivo. Moreover, compound (3d) demonstrated less ulcerogenicity in rats as compared to aspirin. The selectivity of the most promising compound (3d) for COX-1 and COX-2 enzymes was determined with the help of molecular docking studies and the results were correlated with the biological activity.     

Synthesis,antitumor and antimicrobial activity of some new 6-methyl-3-phenyl-4(3H)-quinazolinone analogues: in silico studies

Some new derivatives of substituted-4(3H)-quinazolinones were synthesized and evaluated for their in vitro antitumor and antimicrobial activities. The results of this study demonstrated that compound 5 yielded selective activities toward NSC Lung Cancer EKVX cell line, Colon Cancer HCT-15 cell line and Breast Cancer MDA-MB-231/ATCC cell line, while NSC Lung Cancer EKVX cell line and CNS Cancer SF-295 cell line were sensitive to compound 8. Additionally, compounds 12 and 13 showed moderate effectiveness toward numerous cell lines belonging to different tumor subpanels. On the other hand, the results of antimicrobial screening revealed that compounds 1, 9 and 14 are the most active against Staphylococcus aureus ATCC 29213 with minimum inhibitory concentration (MIC) of 16, 32 and 32?μg/mL respectively, while compound 14 possessed antimicrobial activities against all tested strains with the lowest MIC compared with other tested compounds. In silico study, ADME-Tox prediction and molecular docking methodology were used to study the antitumor activity and to identify the structural features required for antitumor activity.     

Some coumarins and benzoxazinones as potent paraoxonase 1 inhibitors

In this study, we aimed to investigate the effect of some coumarin and benzoxazinone derivatives on the activity of human PON1. Human serum paraoxonase 1 was purified from fresh human serum blood by two-step procedures that are ammonium sulfate precipitation (60–80%) and then hydrophobic interaction chromatography (Sepharose 4B, L-tyrosine and 1-napthylamine). The enzyme was purified 232-fold with a final specific activity of 27.1?U/mg. In vitro effects of some previously synthesized ionic coumarin or benzoxazinone derivatives (1–21) on purified PON1 activity were investigated. Compound 14 (1-(2,3,4,5,6)-pentamethylbenzyl-3-(6,8-dimethyl-2H-chromen-2-one-4-yl))benzimidazolium chloride was found out as the strongest inhibitor (IC₅₀?=?7.84?μM) for PON1 among the compounds. Kinetic investigation and molecular docking study were evaluated for one of the most active compounds (compound 12) and obtained data showed that this compound is competitive inhibitor of PON1 and interact with Leu262 and Ser263 in the active site of PON1. Moreover, coumarin derivatives were found out as the more potent inhibitors for PON1 than benzoxazinone derivatives.     

Synthesis of α-oxycarbanilinophosphonates and their anticholinesterase activities: the most potent derivative is bound to the peripheral site of acetylcholinesterase

A novel method has been developed for the synthesis of α-oxycarbanilino phosphonates through a reaction of α-hydroxyphosphonates with isocyanate under microwave irradiation. The synthesized compounds were evaluated for their acetylcholinesterase (AChE) inhibition potency through IC₅₀determination. Molecular modelling studies suggest that the most potent inhibitor (compound 4h, IC₅₀ = 6.36 µM) is bound to the peripheral site of AChE, which suggests that it decreases the catalytic activity not through binding to the active site but through blocking the entrance of the active site gorge. This puts forward the potential of compound 4h and its derivatives to be used in the design of dual inhibitors: inhibition of the catalytic activity of AChE and of amyloid β aggregation.     

Synthesis and Antileishmanial Activity of 3-Imidazolylalkylindoles. Part I

The present study was designed to investigate conazoles as new antileishmanial agents. Several 3-imidazolylalkylindoles were prepared under mild reaction conditions and pharmacomodulation at N1 and C5 of the indole ring and at the level of the alkyl chain (R) was carried out starting from the corresponding 3-formylindoles 7–10. All target imidazolyl compounds 38–52 were evaluated in vitro against Leishmania mexicana promastigotes; ketoconazole, amphotericin B and meglumine antimoniate were used as references. Eight out of fifteen compounds (40, 43, 44, 47, 48, 50, 51 and 52) exerted similar activity to ketoconazole, with IC₅₀ values in the range of 2.10–3.30?μg/mL. However the most potent compound, 1-(2-bromobenzyl)-3-(1H-imidazol-1-ylmethyl)-1H-indole (38), exhibited IC₅₀ value (0.011±0.003?μg/mL) 270-fold lower than that of ketoconazole. Four compounds (38, 43, 50 and 52) were also tested against intracellular amastigotes of L. mexicana; compound 38 exhibited the highest activity with an IC₅₀ value of 0.018±0.004?μg/mL.