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New 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were synthesized as cannabinoid (CB) receptor ligands. Compound 11 (CB(1)K(i) = 2.3 nM, CB(1) SI = 163.6) showed CB(1) receptor affinity and selectivity superior to Rimonabant and AM251. Acute administration of 2mg/kg 11 reduced sucrose, but not regular food, intake in rats. On the other hand, compound 23 (CB(2)K(i) = 0.51 nM, CB(2) SI = 30.0) showed significant affinity and selectivity for the CB(2) receptor. The results presented here show that the 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamide may serve as an effective scaffold for the design of either CB(1) or CB(2) receptor ligands.

New indolylarylsulfone derivatives bearing cyclic substituents at indole-2-carboxamide linked through a methylene/ethylene spacer were potent inhibitors of the WT HIV-1 replication in CEM and PBMC cells with inhibitory concentrations in the low nanomolar range. Against the mutant L100I and K103N RT HIV-1 strains in MT-4 cells, compounds 20, 24-26, 36, and 40 showed antiviral potency superior to that of NVP and EFV. Against these mutant strains, derivatives 20, 24-26, and 40 were equipotent to ETV. Molecular docking experiments on this novel series of IAS analogues have also suggested that the H-bond interaction between the nitrogen atom in the carboxamide chain of IAS and Glu138:B is important in the binding of these compounds. These results are in accordance with the experimental data obtained on the WT and on the mutant HIV-1 strains tested.

Background: Novel indolylarylsulfones (lASs), designed through rational structure-based molecular modelling and docking approaches, have been recently characterized as effective inhibitors of the wild-type and drug-resistant mutant HIV-1 reverse transcriptase (RT). Methods: Here, we studied the interaction of selected halo- and nitra-substituted IAS derivatives, with the RT enzyme carrying the single resistance mutations K103N and Y181I through steady-state kinetic experiments. Results: The studied compounds exhibited high selectivity to the mutant RT in complex with its substrates, behaving as uncompetitive inhibitors. The presence of the K103N mutation, and to a lesser extent the Y181I, stabilized the drug interactions with the viral RT, when both its substrates were bound. Conclusions: The characterization of these mutation-specific effects on inhibitor binding might be relevant to the design of more effective new generation non-nucleoside reverse transcriptase inhibitors, with better resilience towards drug resistant mutants.

Chikungunya virus (CHIKV) is an Arbovirus that is transmitted to humans primarily by the mosquito species Aedes aegypti. Infection with this pathogen is often associated with fever, rash and arthralgia. Neither a vaccine nor an antiviral drug is available for the prevention or treatment of this disease. Albeit considered a tropical pathogen, adaptation of the virus to the mosquito species Aedes albopictus, which is also very common in temperate zones, has resulted in recent outbreaks in Europe and the US. In the present study, we report on the discovery of a novel series of compounds that inhibit CHIKV replication in the low μM range. In particular, we initially performed a virtual screening simulation of ∼5million compounds on the CHIKV nsP2, the viral protease, after which we investigated and explored the Structure-Activity Relationships of the hit identified in silico. Overall, a series of 26 compounds, including the original hit, was evaluated in a virus-cell-based CPE reduction assay. The study of such selective inhibitors will contribute to a better understanding of the CHIKV replication cycle and may represents a first step towards the development of a clinical candidate drug for the treatment of this disease. publisher: Elsevier articletitle: Computer-aided identification, design and synthesis of a novel series of compounds with selective antiviral activity against chikungunya virus journaltitle: Antiviral Research articlelink: http://dx.doi.org/10.1016/j.antiviral.2013.01.002 content_type: article copyright: Copyright © 2013 Elsevier B.V. All rights reserved. ispartof: Antiviral Research vol:98 issue:1 pages:12-18 ispartof: location:Netherlands status: published

International audience; We report the first example of venting-while-heating microwave-assisted synthesis of a small library of 3-arylthioindoles. Compounds were prepared in excellent isolated yields (90-98%) within 4 min in a closed vessel by treating indoles with disulfides in the presence of sodium hydride in anhydrous N,N-dimethylformamide. The method was not affected by electron-donating and -withdrawing substituents both on 3-arylthio moiety and at 2- and 5-positions of the indole nucleus.

City distribution plays a key role in supporting urban lifestyles, helping to serve and retain industrial and trading activities, and contributing to the competitiveness of regional industry. Despite these positive effects, it also generates negative (economic, environmental and social) impacts on cities worldwide. Relatively little attention has been paid to these issues by researchers and policymakers until recently. The analyses found in City Distribution and Urban Freight Transport aim to improve knowledge in this important area by recognizing and evaluating the problems, with a focus on urban freight transport systems.

A new microwave-assisted protocol for a very fast synthesis of pyridyl N-aryl hydrazones in open vessel mode, under cooling while heating conditions is developed.

We reported the first example of open vessel and cooling while heating microwave-assisted synthesis of pyridinyl N-aryl hydrazones. Compounds were prepared in excellent isolated yields (88-98%) in only 5 min, by reacting 4- and 2,4-(di)substituted phenylhydrazines, bearing both electron-donating (4-CH₃, 4-OCH₃) and -withdrawing (4-Cl, 4-Br, 4-CF₃, 4-NO₂, 2,4-Cl₂) groups with 2-, 3-, and 4-acetylpyridine. The method was successfully extended to other carbonyl compounds.

New arylthioindoles (ATIs) were obtained by replacing the 2-alkoxycarbonyl group with a bioisosteric 5-membered heterocycle nucleus. The new ATIs 5, 8, and 10 inhibited tubulin polymerization, reduced cell growth of a panel of human transformed cell lines, and showed higher metabolic stability than the reference ester 3. These compounds induced mitotic arrest and apoptosis at a similar level as combretastatin A-4 and vinblastine and triggered caspase-3 expression in a significant fraction of cells in both p53-proficient and p53-defective cell lines. Importantly, ATIs 5, 8, and 10 were more effective than vinorelbine, vinblastine, and paclitaxel as growth inhibitors of the P-glycoprotein-overexpressing cell line NCI/ADR-RES. Compound 5 was shown to have medium metabolic stability in both human and mouse liver microsomes, in contrast to the rapidly degraded reference ester 3, and a pharmacokinetic profile in the mouse characterized by a low systemic clearance and excellent oral bioavailability.

A series of N-alkyl 1-ary1-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were synthesized as new ligands of the human recombinant receptor hCB(1). n-Alkyl carboxamides brought out different SARs from the branched subgroup. Unsubstituted pyrrole derivatives bearing a tert-alkyl chain at the 3-carboxamide nitrogen showed greater hCB1 receptor affinity than the corresponding unbranched compounds. In particular, the tert-butyl group as a chain terminal moiety strongly improved hCB(1) receptor affinity (compound 24: K(i); = 45.6 nM; 29: K(i) = 37.5 nM). Acute administration of either compound 12 or 29 resulted in a specific, dose-dependent reduction in food intake in rats. Such results provide an useful basis for the design of new CB(1) ligands. (C) 2010 Elsevier Masson SAS. All rights reserved.

New arylthioindoles along with the corresponding ketone and methylene compounds were potent tubulin assembly inhibitors. As growth inhibitors of MCF-7 cells, sulfur derivatives were superior or sometimes equivalent to the ketones, while methylene derivatives were substantially less effective. Esters 24, 27-29, 36, 39, and 41 showed approximately 50% of inhibition on human HeLa and HCT116/chr3 cells at 0.5 microM, and these compounds inhibited the growth of HEK, M14, and U937 cells with IC(50)'s in the 78-220 nM range. While murine macrophage J744.1 cell growth was significantly less affected (20% at higher concentrations), four other nontransformed cell lines remained sensitive to these esters. The effect of drug treatment on cell morphology was examined by time-lapse microscopy. In a protocol set up to evaluate toxicity on the Saccharomyces cerevisiae BY4741 wild type strain, compounds 24 and 54 strongly reduced cell growth, and 29, 36, and 39 also showed significant inhibition.

New substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were synthesized by replacing the 2,4-dichlorobenzyl and cyclohexyl moieties at the 3-carboxamide nitrogen of the previously reported CB(1) receptor antagonists/inverse agonists 4 and 5. Several ligands showed potent affinity for the hCB(1) receptor, with K(i) concentrations comparable to the reference compounds 1, 4 and 5, and exhibited CB(1) selectivity comparable to 1 and 2. Docking experiments and molecular dynamics (MD) simulations explained the potent hCB(1) binding affinity of compounds 31 and 37. According to our previous studies, 31 and 37 formed a H-bond with K3.28(192), which accounted for the high affinity for the receptor inactive state and the inverse agonist activity. The finding of inhibition of food intake following their acute administration to rats, supported the concept that the CB(1) selective compounds 4 and 52 act as antagonists/inverse agonists.

New monoamine oxidase inhibitors were synthesized as indole analogues of a previously reported pyrrole series. Several compounds were potent MAO-A (12, 17, 19-22, 31, 36, and 37) or MAO-B (14, 20, 24, 38, 44, and 46) inhibitors, and had K(i) values in the nanomolar concentration range. In particular, 22 (K(i)=0.00092 microM, and SI=68,478) was exceptionally potent and selective as MAO-A inhibitor. In molecular modeling studies, compounds 22, 24, 44, and 46 positioned the indole ring into an aromatic cavity of MAO-A, and established pi-pi stacking interactions with Tyr407, Tyr444, and FAD cofactor. However, only compound 22 was able to form hydrogen bonds with FAD, a finding which was in accordance with its potent anti-MAO-A activity. Conversely, 22/MAOB complex was highly unstable during the MD simulation.

City distribution plays a key role in supporting urban lifestyles, helping to serve and retain industrial and trading activities, and contributing to the competitiveness of regional industry. Despite these positive effects, it also generates negative (economic, environmental and social) impacts on cities worldwide. Relatively little attention has been paid to these issues by researchers and policymakers until recently. The analyses found in City Distribution and Urban Freight Transport aim to improve knowledge in this important area by recognizing and evaluating the problems, with a focus on urban freight transport systems.