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This work was supported by the by the Fondation de France (comite Parkinson), the Agence Nationale de la Recherche (ANR-05-NEUR-0121-02, ANR-07-NEURO-047-04, and ANR-08-NEUR-006-02 in the frame of ERA-NET NEURON and ANR-13-BSV1-0006), the Fondation pour la Recherche Medicale (INE200S0303431 and FRM team DEQ20130326522 to J.P.P.), the CNRS (Direction de l'Innovation et des Relations avec les Entreprises), the Neuropole de Recherche Francilien (NeRF), the Ministere de l'Education Nationale de la Recherche et de la Technologie, Retina, France. The Pharmacological assays on recombinant mGlu receptors were performed at the ARPEGE (Pharmacology Screening Interactome) platform facility at the Institute of Functional Genomics (Montpellier, France), which we are thankful., A group III metabotropic glutamate (mGlu) receptor agonist (PCEP) was identified by virtual HTS. This orthosteric ligand is composed by an L-AP4-derived fragment that mimics glutamate and a chain that binds into a neighboring pocket, offering possibilities to improve affinity and selectivity. Herein we describe a series of derivatives where the distal chain is replaced by an aromatic or heteroaromatic group. Potent agonists were identified, including some with a mGlu(4) subtype preference, e.g., 17m (LSP1-2111) and 16g (LSP4-2022). Molecular modeling suggests that aromatic functional groups may bind at either one of the two chloride regulatory sites. These agonists may thus be considered as particular bitopic/dualsteric ligands. 17m was shown to reduce GABAergic synaptic transmission at striatopallidal synapses. We now demonstrate its inhibitory effect at glutamatergic parallel fiber-Purkinje cell synapses in the cerebellar cortex. Although these ligands have physicochemical properties that are markedly different from typical CNS drugs, they hold significant therapeutic potential., Fondation de France; Agence Nationale de la Recherche [ANR-05-NEUR-0121-02, ANR-07-NEURO-047-04, ANR-08-NEUR-006-02, ANR-13-BSV1-0006]; Fondation pour la Recherche Medicale [INE200S0303431, DEQ20130326522]; CNRS (Direction de l'Innovation et des Relations avec les Entreprises); Neuropole de Recherche Francilien (NeRF); Ministere de l'Education Nationale de la Recherche et de la Technologie, Retina, France

Novel classes of CB2 agonists based on 4-oxo-1,4-dihydroquinoline and 4-oxo-1,4-dihydro-1,5-, -1,6- and -1,8-naphthyridine scaffolds have shown high binding affinity toward CB2 receptor and good selectivity over CB1. A computational study of comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) was performed, in order to identify the key structural features impacting their binding affinity. The final CoMSIA model resulted to be the more predictive, showing \( r_{ncv}^2 = 0.84 \), \( r_{cv}^2 = ~0.619 \), SEE = 0.369, and \( r_{pred}^2 = 0.75 \). The study provides useful suggestions for the synthesis of new selective analogues with improved affinity.

In order to further explore the antiproliferative properties of O-phenoxyethyl and O-adamantyl acylthiocarbamates (ATCs), a series of 14 derivatives was prepared by a parallel adaptation of a highly convergent one-pot three-step procedure. Ten acylthiocarbamates were selected by the National Cancer Institute drug evaluation program and screened against a panel of 55 to 58 cell lines derived from nine different types of human cancers. In general, the tested compounds showed a widespread micromolar activity with some specificity against leukemia, renal UO-31, central nervous system (CNS) SNB-75, and non-small cell lung HOP-92 cancer cell lines. Bioinformatic COMPARE analyses were carried out to identify possible mechanism(s) of action for acylthiocarbamate antiproliferative activity.

A series of 6-amino-4-oxo-1,3-diphenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonyl derivatives was synthesized. The compounds demonstrated to be novel, potent and selective inhibitors of Interleukin-8-induced human neutrophil chemotaxis. A SAR study was performed by varying the carbonyl function at position 5 and the chain linked to the amino group at position 6 of the scaffold. All the compounds of the series displayed inhibitory activity at nano- or picomolar concentrations against Interleukin-8-driven migration and no activity against fMLP- and C5a-induced chemotaxis. The binding tests of selected compounds on CXCR1 and CXCR2 receptors were negative. The most potent derivative showed in vivo efficacy in a mouse model of Zymosan-induced peritonitis.

The structure–activity relationships (SARs) of acylthiocarbamates (ATCs), a new class of non-nucleoside HIV-1 reverse transcriptase inhibitors, have been expanded. Sixty-six new analogues were prepared by parallel solution-phase synthesis. In general, the potency of new ATCs was better than that of the first series and O -[2-phthalimidoethyl] 4-chlorophenyl(3-nitrobenzoyl) thiocarbamate turned out to be the most potent ATC so far synthesized (EC 50 = 1.5 nM). Several ATCs were active at micromolar concentrations against HIV-1 strains carrying the RT Y181C mutation and one of them was also moderately active against the K103R variant. Docking simulations were carried out to rationalize the most relevant SARs.

In order to expand the structure-activity relationship (SAR) studies on Thiocarbamates (TCs), a recently discovered class of potent non-nucleoside HIV-1 reverse transcriptase inhibitors, 38 analogues of the lead O-[2-(2-pyridyl)ethyl]-N-phenylthiocarbamate 1 were prepared by parallel solution-phase synthesis. The SAR strategy was focused on the variation (mono- and disubstitution) of the N-phenyl ring and the replacement of the 2-pyridyl with 4-pyridyl, 2-thienyl and phenyl rings. The majority of the new TCs proved to prevent the wild-type HIV-1 multiplication in MT-4 cell culture and the most potent congeners displayed an EC(50) value of 100 nM. Two TCs were active also at micromolar concentrations against the Y181C- and/or K103N/Y181C-resistant mutants. Docking simulations helped to rationalize the SARs.

Oxadiazoles were generated upon a dehydrative cyclization reaction with 2-acyl hydrazides bound to the polymeric support via one of their N atoms using TFAA as a dehydration agent.

(R)-PCEP (3-amino-3-carboxypropyl-2'-carboxyethyl phosphinic acid, 1), a new metabotropic glutamate receptor 4 (mGlu4R) agonist, was discovered in a previously reported virtual screening. The (S)-enantiomer and a series of derivatives were synthesized and tested on recombinant mGlu4 receptors. A large number of derivatives activated this receptor but was not able to discriminate between mGlu4 and mGlu8 receptors. The most potent ones 6 and 12 displayed an EC(50) of 1.0 +/- 0.2 microM at mGlu4R. Interestingly these agonists with longer alkyl chains revealed a new binding pocket adjacent to the glutamate binding site, which is lined with residues that differ among the mGluR subtypes and that will allow the design of more selective compounds. Additionally 6 was able to activate mGlu7 receptor with an EC(50) of 43 +/- 16 microM and is thus significantly more potent than L-AP4 (EC(50) of 249 +/- 106 microM).

The structural simplification of the non-nucleoside reverse transcriptase inhibitors (NNRTIs) O-(2-phthalimidoethyl)-N-(hetero)aroyl-N-arylthiocarbamates led us to design (hetero)aroyl esters of 2-(N-phthalimido)ethanol as a potential new class of anti-HIV-1 agents. The setup of a solution-phase parallel synthesis method allowed the rapid preparation of a high number of analogues. In cell-based assays, 20 of 34 esters showed anti-HIV-1 activity ranging from nanomolar to micromolar concentrations. The most potent esters had only a minor effect or were ineffective in enzyme assay against HIV-1 reverse transcriptase. Variations on the O-(2-phthalimidoethyl) moiety led to compounds devoid of antiretroviral activity, but cytotoxic, in particular those bearing the 4-chloro-3-nitrobenzoyl moiety. The most cytotoxic compound displayed a CC50 value of 1.6 μM.

Novel classes of cannabinoid 2 receptor (CB2) agonists based on 1,2,3,4-tetrahydropyrrolo[3,4-b]indole and benzimidazole scaffolds have shown high binding affinity toward CB2 receptor and good selectivity over cannabinoid 1 receptor (CB1). A computational study of comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) was performed, initially on each series of agonists, and subsequently on all compounds together, in order to identify the key structural features impacting their binding affinity. The final CoMSIA model resulted to be the more predictive, showing cross-validated r2 (rcv2) = 0.680, non cross-validated r2 (rncv2) = 0.97 and test set \( {{\hbox{r}}^2}\left( {{\hbox{r}}_{\rm{pred}}^2} \right) = 0.{93} \). The study provides useful suggestions for the design of new analogues with improved affinity.

In order to further explore the antiproliferative properties of O-phenoxyethyl and O-adamantyl acylthiocarbamates (ATCs), a series of 14 derivatives was prepared by a parallel adaptation of a highly convergent one-pot three-step procedure. Ten acylthiocarbamates were selected by the National Cancer Institute drug evaluation program and screened against a panel of 55 to 58 cell lines derived from nine different types of human cancers. In general, the tested compounds showed a widespread micromolar activity with some specificity against leukemia, renal UO-31, central nervous system (CNS) SNB-75, and non-small cell lung HOP-92 cancer cell lines. Bioinformatic COMPARE analyses were carried out to identify possible mechanism(s) of action for acylthiocarbamate antiproliferative activity.

Fifty-one acylthioureas (ATUs) incorporating imidazolidine-2-thione or its upper cyclohomologue were prepared by parallel synthesis and evaluated against a high number of human cancer cell lines for antiproliferative activity. ATUs 1o (3,5-dichlorobenzoyl), 1s (2-furoyl), 3s (2-furoyl) and 1t (2-thenoyl) displayed activity against leukemia, melanoma LOX IMVI, non-small cell lung NCI-H522, renal 786-0, CAKI-1, SN12C, UO-31 and breast MCF7, MDA-MB-435, T-47D cancer cell lines in the 0.3-9.7 microM concentration range. Compound 14s exhibited selectivity for melanoma SK-MEL-5 (GI(50)

Acylthiocarbamates (ATCs) have been identified as a class of potent non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors. A computational strategy based on molecular docking studies followed by comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) was used to identify the most important features impacting ATC antiretroviral activity. The CoMSIA model proved to be the more predictive, with r 2 ncv = 0.89, r cv 2 = 0.38, standard error of estimate (SEE) = 0.494, F = 84, and r 2 pred = 0.81. The results of these studies will be useful in designing new ATCs with improved potency, also against clinically relevant resistant mutants.

The structure–activity relationships (SARs) of N -aryl- O -(2-phthalimidoethyl)thiocarbamates (C-TCs) and their imide ring-opened congeners (O-TCs) as non-nucleoside HIV-1 reverse transcriptase inhibitors were further investigated. The SAR strategy involved modifications of the N -phenyl ring followed by the hybridization of the most promising N -aryl and O -(2-phthalimidoethyl) substructures. The role of stereochemistry and tert -butyl substitution of the phthalimidoethyl moiety on activity was also investigated. Seventy-six analogues were prepared by parallel solution-phase synthesis. Twenty-two C-TCs displayed nanomolar activity against wild-type HIV-1 and a number of analogues were effective against the Y181C mutant. Compound 56 combined the highest activity so far identified against Y181C (EC 50 = 1.3 μM) with good potency against the K103R mutant (EC 50 = 4.8 μM). Docking simulations helped to rationalize the SARs.

The molecular duplication of non-nucleoside reverse transcriptase inhibitor (NNRTI) O -(2-phthalimidoethyl)– N -arylthiocarbamates (C-TCs) led to the identification of symmetric formimidoester disulfides (DSs) as a novel class of potent NNRTIs. The lead compound 1 [dimer of the isothiocarbamic form of TC O -(2-phthalimidoethyl)– N -phenylthiocarbamate] turned out to prevent the wild-type HIV-1 multiplication in MT-4 cell culture with an EC 50 value of 0.35 μM. In order to perform a structure–activity relationship (SAR) study, we prepared 40 analogues of 1 by an unprecedented one-pot method of solution-phase parallel synthesis. The SAR strategy was focused on the variation of the N -aryl portion (mono-, di- and trisubstitution of the phenyl ring and its replacement with a 1-naphthyl, cyclopropyl or benzyl group) and of the 2-phthalimidoethyl moiety (introduction of a methyl on the phthalimide substructure, replacement of the phthalimide moiety with a phenyl ring and elongation of the ethyl linker). Most DSs proved to inhibit the wild-type HIV-1 replication in cell-based assays and 15 of them were active at nanomolar concentrations. The most potent congeners ( 11 , 15 , 16 , 17 , 18 , 19 , 20 and 32 , EC 50 : 10–70 nM) shared the N - para -substituted phenyl moiety. Compound 17 tested in enzyme assay against recombinant wild-type reverse transcriptase displayed an IC 50 value of 0.74 μM. Compounds 19 and 33 were active at micromolar concentrations against the clinically relevant Y181C and/or K103R resistant mutants.

To acquire further insight into the structure-activity relationship (SAR) of the thiocarbamates (TCs) described in the preceding work, 57 analogues of the lead compound O-(2-phenylethyl)-N-phenylthiocarbamate I were prepared by parallel solution-phase synthesis. We varied the 2-phenylethyl moiety (mono-substitution on the phenyl ring and modification of the ethyl linker), keeping constant the N-phenyl ring substitutions which have given the best results in the previous series. Most of the new TCs inhibited wild-type HIV-1 at micro- and nanomolar concentrations in MT-4 cell-based assays. Some TCs were also active at micromolar concentrations against the Y181C and/or K103N/Y181C resistant mutants. The SARs were rationalized by docking simulations.

Thiocarbamates (TCs) have been recently identified as a new class of potent non-nucleoside HIV-1 Reverse Transcriptase (RT) inhibitors. A computational strategy based on molecular docking studies, followed by CoMFA and CoMSIA analyses, has been used to elucidate the atomic details of the RT/TC interactions and to identify the most important features impacting the TC antiretroviral activity. The CoMFA model resulted to be the more predictive, and gave r(2)=0.93, r(cv)(2)=0.53, SEE=0.292, F=180, and r(test)(2)=0.70. The 3D-QSAR field contributions and the structural features of the RT binding site showed a good correlation. These studies will be useful to design new TCs with improved potency also against clinically relevant resistant mutants.

A facile stereoselective synthesis of Knoevenagel-type compounds 8 and 9 was accomplished through a one-pot two-step procedure. The reaction of ethylenethiourea ( 1) and ethyleneurea ( 2) with benzoyl chloride- N, N-dimethylformamide complex in N, N-dimethylformamide gave the corresponding isolable ternary N-methyleniminium chlorides 3 and 4, along with benzoic acid ( 5) as a byproduct. Hydrolysis of salts 3 and 4 yielded the N-formyl derivatives 6 and 7, thus confirming the N-methyleniminium structure. Salts 3 and 4 condensed in situ at 120 °C with a variety of acyclic active methylene reagents Y-CH 2 -Z (Y = or ≠ Z), in the presence of 5 (Procedure A) or of 5 and triethylamine (1.5 equiv) (Procedure B), afforded α,β-unsaturated compounds 8 and 9. The overall yields ranged from poor to good. Mechanistic hypotheses concerning the formation of 3 and 4 and the origin of the stereoselectivity are also discussed.

In the crystal structure of the novel acyl­thio­carbamate derivative O-[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)­ethyl] N-(4-methyl­phenyl)-N-(3-nitro­benzoyl)thio­carbamate, C25H19N3O6S, intra- and inter­molecular π–π inter­actions occur between the phthalimide and N-benzoyl moieties. The partial atomic charges, calculated by ab initio methods, are consistent with the observed structure.

In this paper we describe our structure-based ligand design, synthetic strategy, and structure-activity relationship (SAR) studies that led to the identification of thiocarbamates (TCs), a novel class of non-nucleoside reverse transcriptase inhibitors (NNRTIs), isosteres of phenethylthiazolylthiourea (PETT) derivatives. Assuming as a lead compound O-[2-(phthalimido)ethyl]phenylthiocarbamate 12, one of the precursors of the previously described acylthiocarbamates (Ranise, A.; et al. J. Med. Chem. 2003, 46, 768-781), two targeted solution-phase TC libraries were prepared by parallel synthesis. The lead optimization strategy led to para-substituted TCs 31, 33, 34, 39, 40, 41, 44, 45, and 50, which were active against wild-type HIV-1 in MT-4-based assays at nanomolar concentrations (EC50 range: 0.04-0.01 microM). The most potent congener 50 (EC50 = 0.01 microM) bears a methyl group at position 4 of the phthalimide moiety and a nitro group at the para position of the N-phenyl ring. Most of the TCs showed good selectivity indices, since no cytotoxic effect was detected at concentrations as high as 100 microM. TCs 31, 37, 39, 40, and 44 significantly reduced the multiplication of the Y181C mutant, but they were inactive against K103R and K103N + Y181C mutants. Nevertheless, the fold increase in resistance of 41 was not greater than that of efavirenz against the K103R mutant in enzyme assays. The docking model predictions were consistent with in vitro biological assays of the anti-HIV-1 activity of the TCs and related compounds synthesized.