Analogs of arachidonic acid methylated at C-7 and C-10 inhibit leukotriene biosynthesis and phospholipase A2 activity

The ability of (all Z)-7,7-dimethyl-5,8,11,14-eico-satetraenoic acid, (all Z)-7,7-dimethyl-5,8,11-eicosatrienoic acid, (Z,Z)-7,7-dimethyl-5,8-eicosadienoic acid, (all Z)-10,10-dimethyl-5,8,11,14-eicosatetraenoic acid, (all Z)-10,10-dimethyl-5,8,11-eicosatrienoic acid, and rac-(Z,Z)-15-hydroxy-7,7-dimethyl-5,8-eicosadienoic acid to inhibit ionophore-induced slow-reacting substance of anaphylaxis (SRS-A) biosynthesis in rat peritoneal cells was studied. It was thought that compounds such as these might inhibit proton abstractions at the 7 or 10 carbon positions on arachidonic acid which are thought to be important in the mechanism of catalysis of Δ⁵-lipoxygenase(Δ⁵-LO). All compounds were found to be potent inhibitors of SRS-A biosynthesis in the in vitro rat peritoneal cell system (IC₅₀ < 10 μM). In fact they were more potent inhibitors in the test system than standard Δ⁵-LO inhibitors such as NDGA and quercetin. To determine if the mechanism of inhibition of the dimethyl arachidonic acid analogs did involve gD⁵-LO inhibition these compounds were evaluated in an assay system utilizing the Δ⁵-LO from rat basophilic leukemia (RBL^?1_cells. It was found, however, that these compounds were much less potent inhibitors of this enzyme (IC₅₀ ～ 100 μM) than standard compounds such as NDGA (IC₅₀ 0.14 μM) and quercetin (IC₅₀, 0.2 μM). The arachidonic acid analogs were subsequently found to be potent inhibitors of phospholipase A₂ (PLA₂) enzymes with IC₅₀'s between 10–20 μM as inhibitors of a snake venom enzyme. In fact these compounds are among the most potent inhibitors of PLA₂ yet studied, having potencies better than standards such as p-bromophenacyl bromide (IC₅₀, 87 μM) and U-10029A (IC₅₀, 36 μM). These results suggest that the methylated arachidonic acid analogs may inhibit SRS-A biosynthesis through inhibiting PLA₂.     

Synthesis and insecticidal evaluation of novel anthranilic diamides containing N-substitued nitrophenylpyrazole

To cope with developing pest resistance and ecological problems associated with conventional insecticides and to search for potent insecticides targeting at ryanodine receptor (RyR), a series of novel anthranilic diamides containing N-substitued nitrophenylpyrazole were designed and synthesized. The insecticidal activities of target compounds against oriental armyworm (Mythimna separata) and diamondback moth (Plutella xylostella) were evaluated in our greenhouse by bio-assay tests and the relative structure–activity relationships were briefly discussed. Most compounds exhibited moderate to high activities, in which G₇ and K₅ showed high activity against oriental armyworm and K₂ and K₄ against diamondback moth even better than the control-chlorantraniliprole. The calcium imaging technique was used to investigate the effects of several typical title compounds on the [Ca²⁺]_i, especially the effects of G₇ on the intracellular calcium ion concentration ([Ca²⁺]_i) in neurons, which indicated that some title compounds were potent activators of the RyR.     

Design,synthesis and herbicidal activity study of aryl 2,6-disubstituted sulfonylureas as potent acetohydroxyacid synthase inhibitors

A series of sulfonylurea derivatives containing a 2,6-disubstituted aryl moiety were designed, synthesized and evaluated for their herbicidal activities. Most of these compounds showed excellent inhibitory rates against both monocotyledonous and dicotyledonous weeds, especially 10a, 10h and 10i. They exhibited equivalent or superior herbicidal efficiency than commercial chlorsulfuron at the dosage of 15 g/ha and the preliminary SAR was summarized. In order to illuminate the molecular mechanism of several potent compounds, their apparent inhibition constant (K_i^app) of Arabidopsis thaliana acetohydroxyacid synthase (AHAS) were determined and the results confirmed that these compounds were all potent AHAS inhibitors. 10i have a K_i^app of 11.5 nM, which is about 4 times as potent as chlorsulfuron (52.4 nM).     

Design,synthesis, evaluation,and molecular docking of ursolic acid derivatives containing a nitrogen heterocycle as anti-inflammatory agents

Ursolic acid derivatives containing oxadiazole, triazolone, and piperazine moieties were synthesized in an attempt to develop potent anti-inflammatory agents. Structures of the synthesized compounds were elucidated by ¹H NMR, ¹³C NMR, and HRMS. Most of the synthesized compounds showed pronounced anti-inflammatory effects at 100?mg/kg. In particular, compound 11b, which displayed the most potent anti-inflammatory activity of all of the compounds prepared, with 69.76% inhibition after intraperitoneal administration, was more potent than the reference drugs indomethacin and ibuprofen. The cytotoxicity of the compounds was also assessed by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and no compounds showed any appreciable cytotoxic activity (IC₅₀ >100?μmol/L). Furthermore, molecular docking studies of the synthesized compounds were performed to rationalize the obtained biological results. Overall, the results indicate that compound 11b could be a therapeutic candidate for the treatment of inflammation.     

N-(Phenoxyalkyl)amides as MT1 and MT2 ligands: Antioxidant properties and inhibition of Ca2+/CaM-dependent kinase II

Recently a series of chiral N-(phenoxyalkyl)amides have been reported as potent MT₁ and MT₂ melatonergic ligands. Some of these compounds were selected and tested for their antioxidant properties by measuring their reducing effect against oxidation of 2′,7′-dichlorodihydrofluorescein (DCFH) in the DCFH-diacetate (DCFH-DA) assay. Among the tested compounds, N-[2-(3-methoxyphenoxy)propyl]butanamide displayed potent antioxidant activity that was stereoselective, the (R)-enantiomer performing as the eutomer. This compound displayed strong cytoprotective activity against H₂O₂-induced cytotoxicity resulting slightly more active than melatonin, and performed as Ca²⁺/calmodulin-dependent kinase II (CaMKII) inhibitor, too.     

Oxindole based oxadiazole hybrid analogs: Novel α-glucosidase inhibitors

Inhibition of α-glucosidase is an effective strategy for controlling post-prandial hyperglycemia in diabetic patients. Beside these α-glucosidase inhibitors has been also used as anti-obesity and anti-viral drugs. Keeping in view the greater importance of α-glucosidase inhibitors here in this study we are presenting oxindole based oxadiazoles hybrid analogs (1–20) synthesis, characterized by different spectroscopic techniques including ¹H NMR and EI-MS and their α-glucosidase inhibitory activity. All compounds were found potent inhibitors for the enzyme with IC₅₀ values ranging between 1.25 ± 0.05 and 268.36 ± 4.22 µM when compared with the standard drug acarbose having IC₅₀ value 895.09 ± 2.04 µM. Our study identifies novel series of potent α-glucosidase inhibitors and further investigation on this may led to the lead compounds. A structure activity relationship has been established for all compounds. The interactions of the active compounds and enzyme active site were established with the help of molecular docking studies.     

Synthesis of novel 5-amino-1,3,4-thiadiazole-2-sulfonamide containing acridine sulfonamide/carboxamide compounds and investigation of their inhibition effects on human carbonic anhydrase I,II, IV and VII

Herein, we report that acridine intermediates 5 were obtained from the reduction of nitro acridine derivatives 4, which were synthesized via condensation of dimedone, p-nitrobenzaldehyde with 4-amino-N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)benzamide, respectively. Then acridine sulfonamide/carboxamide (7a–i) compounds were synthesized by reaction of amino acridine 5 with sulfonyl chlorides and carbamoyl chlorides. The new compounds were characterized by melting points, FT-IR, ¹H NMR, ¹³C NMR and HRMS analyzes. The evaluation of in vitro test of the synthesized compounds against hCA I, II, IV and VII showed that some of them are potent inhibitors. Among them, compound 7e showed the most potent activity against hCA II with a K_I of 7.9 nM.     

Design,synthesis and anticancer evaluation of 1H-pyrazolo[3,4-d]pyrimidine derivatives as potent EGFRWT and EGFRT790M inhibitors and apoptosis inducers

In our attempt to develop effective EGFR-TKIs, two series of 1H-pyrazolo[3,4-d]pyrimidine derivatives were designed and synthesized. All the newly synthesized compounds were evaluated in vitro for their inhibitory activities against EGFR^WT. Compounds 15_b, 15_j, and 18_d potently inhibited EGFR^WT at sub-micro molar IC₅₀ values comparable to that of erlotinib. Moreover, thirteen compounds that showed promising IC₅₀ values against EGFR^WT were tested in vitro for their inhibitory activities against mutant EGFR^T790M. Compounds 17_d and 17_f exhibited potent inhibitory activities towards EGFR^T790M comparable to osimertinib. Compounds that showed promising IC₅₀ values against EGFR^WT were further tested for their anti-proliferative activities against three cancer cell lines bearing EGFR^WT (MCF-7, HepG2, A549), and two cancer cell lines bearing EGFR^T790M (H1975 and HCC827). Compounds 15_g, 15_j, 15_n, 18_d and 18_e were the most potent anticancer agents against the EGFR^WT containing cells, while compounds 15_e, 17_d and 17_f showed promising anti-proliferative activities against EGFR^T790M containing cells. Furthermore, the most active compound 18_d was selected for further studies regarding to its effects on cell cycle progression and induction of apoptosis in the HepG2 cell line. The results indicated that this compound is good apoptotic agent and arrests G₀/G₁and G₂/M phases of cell cycle. Finally, molecular docking studies were performed to investigate binding pattern of the synthesized compounds with the prospective targets, EGFR^WT (PDB: 4HJO) and EGFR^T790M (PDB: 3W2O).     

Comparison of the genetic activity of aflatoxins B1 and G1 in Escherichia coli and Saccharomyces cerevisiae

The ability of aflatoxins B₁ and G₁ to induce back mutations to arg⁺ in Escherichia coli K-12/343/113 was compared with induction of mitotic gene conversion to ade⁺ in the diploid yeast strain Saccharomyces cerevisiae D4, ade₂^?. In analogy to previous results with other microorganisms, the compounds were not genetically active per se, indicating that under the experimental conditions employed none of the tester strains were able to activate the compounds to mutagenic products.In experiments using liver homegenates (S-9 fraction) of male Golden Syrian hamsters previously treated with phenobarbital, aflatoxin B₁ exhibited strong genetic activity both in E. coli and in S. cerevisiae, whereas the mutagenic activity of aflatoxin G₁ was markedly lower and could be detected only in the E. coli tester strain. These results correlate the findings that aflatoxin G₁ is a less potent carcinogen and mutagen than aflatoxin B₁.     

Antifouling potential of the marine microalga Dunaliella salina

Marine organisms have usually been viewed as sources of environmentally friendly compounds with antifouling activity. We performed a series of operations to investigate the antifouling potential of the marine microalga Dunaliella salina. For the ethyl acetate crude extract, the antialgal activity was significant, and the EC₅₀ value against Skeletonema costatum was 58.9 μg ml^?1. The isolated purified extract was tested for antifouling activity, the EC ₅₀ value against S. costatum was 21.2 μg ml^?1, and the LC₅₀ against Balanus amphitrite larvae was 18.8 μg ml^?1. Subsequently, both UHR–TOF–MS and GC–MS were used for the structural elucidation of the compounds, and a series of unsaturated and saturated 16- and 18-carbon fatty acids were detected. The data suggested that the fatty acid extracts from D. salina possess high antifouling activity, and could be used as substitutes for potent, toxic antifouling compounds.     

Synthesis of new N-(arylcyclopropyl)acetamides and N-(arylvinyl)acetamides as conformationally-restricted ligands for melatonin receptors

N-(Arylcyclopropyl)acetamides and N-(arylvinyl)acetamides or methyl ureas have been prepared as constrained analogues of melatonin. The affinity of these new compounds for chicken brain melatonin receptors and recombinant human MT₁ and MT₂ receptors was evaluated using 2-[¹²⁵I]-iodomelatonin as radioligand. Strict ethylenic or cyclopropyl analogues of the commercialized agonist agomelatine (Valdoxan®) were equipotent to agomelatine in binding bioassays. However, the ethylenic analogue was more effective than the cyclopropyl one in the melanophore aggregation bioassay, but was still less potent than the disubstituted 2,7-dimethoxy-naphtalenic compounds.     

Flavonols and 4-thioflavonols as potential acetylcholinesterase and butyrylcholinesterase inhibitors: Synthesis,structure-activity relationship and molecular docking studies

To explore new scaffolds for the treat of Alzheimer’s disease appears to be an inspiring goal. In this context, a series of varyingly substituted flavonols and 4-thioflavonols have been designed and synthesized efficiently. All the newly synthesized compounds were characterized unambiguously by common spectroscopic techniques (IR, ¹H-, ¹³C NMR) and mass spectrometry (EI-MS). All the derivatives (1–24) were evaluated in vitro for their inhibitory potential against cholinesterase enzymes. The results exhibited that these derivatives were potent selective inhibitors of acetylcholinesterase (AChE), except the compound 11 which was selective inhibitor of butyrylcholinesterase (BChE), with varying degree of IC₅₀ values. Remarkably, the compounds 20 and 23 have been found the most potent almost dual inhibitors of AChE and BChE amongst the series with IC₅₀ values even less than the standard drug. The experimental results in silico were further validated by molecular docking studies in order to find their binding modes with the active pockets of AChE and BChE enzymes.     

Novel pyrazole integrated 1,3,4-oxadiazoles: Synthesis,characterization and antimicrobial evaluation

A novel series of 2-(5-methyl-1,3-diphenyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazoles 7(a–m) were synthesized either by cyclization of N′-benzoyl-5-methyl-1,3-diphenyl-1H-pyrazole-4-carbohydrazide 4a using POCl₃ at 120 °C or by oxidative cyclization of hydrazones derived from various arylaldehyde and (E)-N′-benzylidene-5-methyl-1,3-diphenyl-1H-pyrazole-4-carbohydrazide 5(a–d) using chloramine-T as oxidant. Newly synthesized compounds were characterized by analytical and spectral (IR, ¹H NMR, ¹³C NMR and LC–MS) methods. The synthesized compounds were evaluated for their antimicrobial activity and were compared with standard drugs. The compounds demonstrated potent to weak antimicrobial activity. Among the synthesized compounds, compound 7m emerged as an effective antimicrobial agent, while compounds 7d, 7f, 7i and 7l showed good to moderate activity. The minimum inhibitory concentration of the compounds was in the range of 20–50 μg mL⁻¹ against bacteria and 25–55 μg mL⁻¹ against fungi. The title compounds represent a novel class of potent antimicrobial agents.     

Synthesis and analgesic effects of novel β2-tryptophan hexapeptide analogs

Aiming to develop more potent analgesic substances a new series of hexapeptides containing β²-tryptophan analogues was synthesized. The Trp in position 4 and 5, respectively in Ac-Arg-Phe-Met-Trp-Met-Lys-NH₂ (opioid receptor antagonist) and Ac-Arg-Tyr-Tyr-Arg-Trp-Lys-NH₂ (highly potent and selective NOP-receptor agonist) was substituted by the (S)-2-(1-methyl-1H-indol-3-yl)propionic residue or the (S)-2-(5-methoxy-1H-indol-3-yl)propionic residue. The analgesic effect of the four newly synthesized compounds has been evaluated in male Wistar rats by PP- and HP tests and compared to the native templates. Further estimation of the mechanisms of action of each compound was achieved using specific antagonists—naloxone for opioid and JTC801 for the NOP receptor. Replacement of Trp with β²-tryptophan analogues in 4th position (Ac-Arg-Phe-Met-Trp-Met-Lys-NH₂) led to increased and longer lasting analgesic effect. The results obtained permit us to assume that both opioid and NOP receptors take part in the newly synthesized compounds analgesic effects.     

Highly efficacious factor Xa inhibitors containing α-substituted phenylcycloalkyl P4 moieties

We previously disclosed a series of highly potent FXa inhibitors bearing α-substituted (CH₂NR¹R²) phenylcyclopropyl P4 moieties in the pyrazolodihydropyridone core system. Herein, we describe our continuous SAR efforts in this series. Effects of the C-3 substitution of the pyrazolodihydropyridone core and the α-substitution (R group) of the cyclopropyl ring on FXa binding affinity (FXa K_i), human plasma anticoagulant activity (PT EC_2×) and permeability are discussed. A set of compounds obtained from optimization of the R group and the C-3 substituent were orally bioavailable in dogs. Furthermore, representative compounds were highly efficacious in the rabbit arterio-venous shunt thrombosis model (EC₅₀s = 29–81 nM).     

Design,synthesis, and evaluation of novel O-alkyl ferulamide derivatives as multifunctional ligands for treating Alzheimer’s disease

Herein, a series of novel O-alkyl ferulamide derivatives were designed and synthesised through the multi-target-directed ligands (MTDLs) strategy. The biological activities in vitro showed that compounds 5a, 5d, 5e, 5f, and 5h indicated significantly selective MAO-B inhibitory potency (IC₅₀ = 0.32, 0.56, 0.54, 0.73, and 0.86 μM, respectively) and moderate antioxidant activity. Moreover, compounds 5a, 5d, 5e, 5f, and 5h showed potent anti-inflammatory properties, remarkable effects on self-induced Aβ_1-42 aggregation, and potent neuroprotective effect on Aβ_1-42-induced PC12 cell injury. Furthermore, compounds 5a, 5d, 5e, 5f, and 5h presented good blood–brain barrier permeation in vitro and drug-like properties. More interesting, the PET/CT images with [¹¹C]5f demonstrated that [¹¹C]5f could penetrate the BBB with a high brain uptake and exhibited good brain clearance kinetic property. Therefore, compound 5f would be a promising multi-functional agent for the treatment of AD.     

Synthesis and anticancer activities of thieno[3,2-d]pyrimidines as novel HDAC inhibitors

A series of thieno[3,2-d]pyrimidines bearing a hydroxamic acid moiety as novel HDAC inhibitors were designed and synthesized. The structures of the new synthesized compounds were confirmed using IR, ¹H, ¹³C NMR spectrum. Compounds 11–13 showed potent inhibitory activities against HDACs with IC₅₀ values at 0.38, 0.49 and 0.61 μM. Most of target compounds displayed strong anti-proliferative activity by a MTT assay on three human cancer cell lines including HCT-116, MCF-7 and HeLa. Compound 11, having potent inhibitory activities against HDACs, induced apoptosis and G2/M cell cycle arrest in HCT-116 cell line.     

Design and discovery of thioether and nicotinamide containing sorafenib analogues as multikinase inhibitors targeting B-Raf,B-RafV600E and VEGFR-2

New sorafenib derivatives containing thioether and nicotinamide moiety were designed and synthesized as B-Raf, B-Raf^V600E and VEGFR-2 multikinase inhibitors. Their in vitro enzymatic inhibitory activities against B-Raf, B-Raf^V600E and VEGFR-2 and their antiproliferative activities against HCT-116 and B16BL6 cell lines were evaluated and described. Most of the compounds showed potent activities against both cell lines and specific kinases. Compounds a1, b1 and c4, which exhibited the most potent inhibitory activities against B-Raf with IC₅₀ of 21?nM, 27?nM and 17?nM, B-Raf^V600E with IC₅₀ of 29?nM, 28?nM and 16?nM, VEGFR-2 with IC₅₀ of 84?nM, 46?nM and 63?nM, respectively, and good antiproliferative activities, also demonstrated competitive antiangiogenic activities to sorafenib in in vitro HUVEC tube formation assay.     

Candenatenins G–K,phenolic compounds from Dalbergia candenatensis heartwood

Five new phenolic compounds, designated candenatenins G–K (1–5), along with four known compounds, were isolated from the heartwood of Dalbergia candenatensis. The structures of these compounds were elucidated by HR-EI-MS, ¹H and ¹³C NMR, COSY, HMQC, HMBC, and NOESY spectra. Compound 5 exhibited potent activity against DPPH radical scavenging with IC₅₀ value of 25.7 μM, whereas compound 2 showed cytotoxicity against NCI-H187 cell line with IC₅₀ value of 14.8 μM.     

Effect of a phenyl group in quaternary ammonium compounds on thiamine uptake in isolated rat hepatocytes

The inhibitory effect of a phenyl group in quaternary ammonium compounds on thiamine uptake in isolated rat hepatocytes was investigated. The phenyltrimethylammonium ion was a more potent inhibitor than the tetramethylammonium ion, while the dibenzyldimethylammonium ion was the most potent inhibitor of thiamine uptake among those compounds examined. A kinetic study showed that this compound was a competitive inhibitor. The cetyltrimethylammonium ion was a less effective inhibitor than the benzyltrimethylammonium ion, and the palmitoylcholine ion was a weak inhibitor. These results indicate that the lipophilicity of a quaternary ammonium compound is not always correlated with its affinity for thiamine-carrier binding, but the presence of a phenyl group plays a significant role in affinity. The inhibitory effect of the series of (CH₃)₃N⁺(CH₂)_nC₆H₅ (n = 0−6) compounds on thiamine uptake in isolated rat hepatocytes was studied. The maximal inhibitory activity occurred at n = 5. These results suggest that the phenyl group in a quaternary ammonium compound has a specific interaction with the thiamine-binding site in rat liver plasma membrane.