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The re-emergence of chikungunya virus (CHIKV) is a serious global health threat. CHIKV is an alphavirus that is transmitted to humans by Aedes mosquitoes; therefore, their wide distribution significantly contributes to the globalization of the disease. Unfortunately, no effective antiviral drugs are available. We have identified a series of 3-aryl-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones as selective inhibitors of CHIKV replication. New series of compounds have now been synthesized with the aim to improve their physicochemical properties and to potentiate the inhibitory activity against different CHIKV strains. Among these newly synthesized compounds modified at position 3 of the aryl ring, tetrahydropyranyl and N-t-butylpiperidine carboxamide derivatives have shown to elicit potent antiviral activity against different clinically relevant CHIKV isolates with 50% effective concentration (EC) values ranging from 0.30 to 4.5 μM in Vero cells, as well as anti-CHIKV activity in human skin fibroblasts (EC = 0.1 μM), a clinically relevant cell system for CHIKV infection., We thank Caroline Collard and Nick Verstraeten for their excellent technical assistance in the acquisition of the antiviral data. This work has been supported by grants from MINECO/ FEDER SAF2015-64629-C2-1-R and by European Union FP7 Program under SILVER grant agreement no. 260644.

Microtubule-targeting agents that bind at the colchicine-site of tubulin are of particular interest in antitumoral therapy due to their dual mechanism of action as antimitotics and vascular disrupting agents. Cyclohexanediones derivatives have been described as a new family of colchicine-domain binders with an association constant to tubulin similar to that of colchicine. Here, the highresolution structures of tubulin in complex with cyclohexanediones TUB015 and TUB075 were solved by X-ray crystallography. A detailed analysis of the tubulin-TUB075 interaction by means of computational affinity maps allowed the identification of two additional regions at the binding site that were addressed with the design and synthesis of a new series of cyclohexanediones with a distal 2-substituted benzofurane. These new compounds showed potent antiproliferative activity with IC50 values in the nM range, arrested cell cycle progression at the G2/M phase and induced apoptosis at sub μM concentrations. Moreover, they caused the destruction of a preformed vascular network in vitro and inhibited the migration of endothelial cells at non-toxic concentrations. Finally, these compounds displayed high affinity for tubulin as substantiated by a Kb value of 2.87 × 108 M−1 which, to the best of our knowledge, represents the highest binding constant measured to date for a colchicine-domain ligand., This project has been supported by the Spanish Ministerio de Economía y Competitividad (SAF2015–64629- C2-1-R to EMP, MJPP. and MJC and SAF2015-64629-C2-2 to F.G.), by the Swiss National Science Foundation (31003A_166608, to MOS) and COST action CM1407 (to MJPP, SL, AP, MS, and JFD). We acknowledge Lizette Van Berckelaer, Eef Meyen and Sam Noppen for excellent technical assistance. We thank V. Olieric and M. Wang for excellent technical assistance with the collection of X-ray data at beamline X06SA of the Swiss Light Source (Paul Scherrer Institut, Villigen PSI, Switzerland). We thank José Fernando Escolar for his help with electron microscopy. We thank ganadería Fernando Díaz for calf brains for tubulin purification. This work was supported in part by grants BFU2016-75319-R (AEI/FEDER, UE) (JFD.) JFD. is a member of the CIB Intramural Program “Molecular Machines for Better Life” (MACBET). We also thank SEQT for the “Ramón Madroñero Award” to O.B.

The allylmagnesium chloride addition/RCM sequence on N-alkenyl-substituted imides provides a mild access to indolizinone and pyrroloazepinone derivatives with the α-hydroxy-γ-lactam framework. The procedure can be applied to the asymmetric synthesis of this type of derivatives, by employing a 2-exo-hydroxy-10-bornylsulfinyl group as a chiral auxiliary. Further functionality can be introduced at the angular position through an α-amidoalkylation reaction.

Carbon-nitrogen bond forming reactions oriented to the synthesis of 2-amino-imidazolidines and imidazoles have been investigated. The C-2 amination of imidazolidinones, via the corresponding 2-chlorodihydroimidazoles, led to 2-benzylaminodihydroimidazole or bis(dihydroimidazole)amino derivatives by choosing the adequate experimental conditions. On the other hand, the use of N-acyl-2-methylsulfanyldihydroimidazoles allowed carrying out the reactions with aromatic amines, such as p-anisidine. Finally, palladium catalyzed BuchwaldHartwig amination was the method of choice for C-N coupling between 2-haloimidazoles and aromatic amines in the synthesis of the corresponding imidazoles.

In this review we summarize recent developments in inter- and intramolecular enantioselective carbolithiation reactions carried out in the presence of a chiral ligand for lithium, such as (-)-sparteine, to promote facial selection on a C=C bond. This is an attractive approach for the construction of new carbon-carbon bonds in an asymmetric fashion, with the possibility of introducing further functionalization on the molecule by trapping the reactive organolithium intermediates with electrophiles. Ministerio de Ciencia e Innovacion (CTQ2009-07733) and Universidad del Pais Vasco/Euskal Herriko Unibertsitatea (UFI11/22, GIU 0946) for their financial support. Technical and personnel support provided by Servicios Generales de Investigacion SGIker (UPV/EHU, MICINN, GV/EJ, ERDF and ESF) is gratefully acknowledged. We also thank UPV/EHU for a postdoctoral grant (A.G).

PT-QSRR models are Quantitative Structure-Reactivity Relationship (QSRR) models based on Perturbation Theory (PT) that may be useful for multi-objective optimization in organic synthesis. In this communication, we summarize some of the more important results and conclusions obtained in our previous research / review paper about PT-QSRR models published in Curr. Top. Med. Chem., 2013, 13, (5), 1713-1741. I this previous work, firstly we reviewed general aspects and applications of both perturbation theory and QSPR models. Secondly, we formulate a general-purpose perturbation theory for multiple-boundary QSPR problems. In this previous work, we developed a new QSPR- Perturbation theory model that classify correctly >100,000 pairs of intra-molecular carbolithiations with 75-95% of Accuracy (Ac), Sensitivity (Sn), and Specificity (Sp). The model predicts probabilities of variations in the yield and enantiomeric excess of reactions due to at least one perturbation in boundary conditions (solvent, temperature, temperature of addition, or time of reaction). The model also account for changes in chemical structure (connectivity structure and/or chirality patterns in substrate, product, electrophile agent, organolithium, and ligand of the asymmetric catalyst).

The intramolecular α-amidoalkylation reactions of aromatic and heteroaromatic ring systems constitute a versatile approach for the synthesis of nitrogen heterocyles in a diastereoselective or enantioselective fashion. On the other hand, the intramolecular reactions of aryllithium compounds have also been extensively used in the synthesis of carbocycles and heterocycles. The use of imides as internal electrophiles is particularly attractive because of the potential to introduce diverse functionality into the cyclized products by subjecting the resulting α-hydroxylactams to intermolecular reactions with nucleophiles through intermediate N-acyliminium cations. This metalation/cyclization/α-amidoalkylation sequence can be diastereocomplementary with intramolecular α-amidoalkylation reactions via N-acyliminium ions derived from the corresponding imides. This review focuses on recent developments of synthetic methods for heterocyclic systems (alkaloids and related systems) based on aryllithium compouns and N-acyliminium ion cyclizations, with special attention to the stereocontrolled formation of carbon–carbon bonds.

Conjugate addition reactions of various types of nucleophiles to the γ-lactam unit of dihydroindolizinone systems have been studied. The addition of cuprates, amines or stabilized carbanions requires the activation of the unsaturated bicyclic lactam with a EWG at C-2, while sulfur-stabilized carbanions are reactive enough to add to the unsubstituted lactam. The stereochemical outcome of the conjugate addition reaction depends on the nature of the substituent at the angular position, and the incoming nucleophile. Thus 1,10b-cis or 1,10b-trans diastereomers could be obtained selectively with dr>95:5. The tandem conjugate addition–alkylation also takes place in good yields. These reactions have been applied to the synthesis of enantiopure tetrahydropyrrolo[2,1- a ]isoquinolines.

BINOL-derived chiral Bronsted acids are capable of carrying out the intramolecular α-amidoalkylation of a tertiary N-acyliminium ions when a methoxylated benzene ring is used as internal π nucleophile. The reaction can be applied to the synthesis of pyrrolo[2,1-a]isoquinolines and use of the sterically congested acid 3e is determinant to obtain good levels of enantioselection.

The synthesis of the title compounds is achieved via alkylmagnesium chloride addition/RCM sequence.

We develop a new QSPR-Perturbation theory model for Synthetic Pathways involving Assymetric Catalysis of Intra-molecular Carbolithiations. In doing so, we used calculated spectral moments of markov electron delocalization matrix for all molecules involved in the reactions. These descriptors and physical variables (temperature etc.) were used to calculate Bob-Jenkins operators that account for perturbations in the synthetic reactions. The model classifies correctly >100,000 pairs of intra-molecular carbolithiations with high Accuracy (Ac), Sensitivity (Sn), and Specificity (Sp). The model predicts probabilities of variations in the yield and enantiomeric excess of reactions due to at least one perturbation in boundary conditions (solvent, temperature,temperature of addition, or time of reaction). The model is useful to predict the effect over synthetic routes of changes in chemical structure (connectivity structure and/or chirality paterns in substrate, product, electrophile agent, organolithium, and ligand of the asymmetric catalyst).

Ring-closing metathesis reactions of dialkenyl amines, amides and carbamates catalyzed by Ru-catalysts provide efficient approaches to six-membered nitrogen heterocyclic compounds, which are precursors of a variety of natural products and related compounds. Abstract Monoterpene indole alkaloids comprise a group of naturally occurring compounds, exhibiting a range of biological activities. These compounds have attracted great attention because of their interesting biosynthetic route and also as a challenging target for total synthesis. For such synthetic approach and structure - activity relationship studies, the knowledge about their absolute stereostructures is essential. This review summarizes the presently available results of studies on the determination of the absolute configuration of indole alkaloids by the use of circular dichroism (CD).

The intramolecular α-amidoalkylation reactions of aromatic and heteroaromatic ring systems constitute a versatile approach for the synthesis of nitrogen heterocyles in a diastereoselective or enantioselective fashion. On the other hand, the intramolecular reactions of aryllithium compounds have also been extensively used in the synthesis of carbocycles and heterocycles. The use of imides as internal electrophiles is particularly attractive because of the potential to introduce diverse functionality into the cyclized products by subjecting the resulting α-hydroxylactams to intermolecular reactions with nucleophiles through intermediate N-acyliminium cations. This metalation/cyclization/α-amidoalkylation sequence can be diastereocomplementary with intramolecular α-amidoalkylation reactions via N-acyliminium ions derived from the corresponding imides. This review focuses on recent developments of synthetic methods for heterocyclic systems (alkaloids and related systems) based on aryllithium compouns and N-acyliminium ion cyclizations, with special attention to the stereocontrolled formation of carbon–carbon bonds.

Conjugate addition reactions of various types of nucleophiles to the γ-lactam unit of dihydroindolizinone systems have been studied. The addition of cuprates, amines or stabilized carbanions requires the activation of the unsaturated bicyclic lactam with a EWG at C-2, while sulfur-stabilized carbanions are reactive enough to add to the unsubstituted lactam. The stereochemical outcome of the conjugate addition reaction depends on the nature of the substituent at the angular position, and the incoming nucleophile. Thus 1,10b-cis or 1,10b-trans diastereomers could be obtained selectively with dr>95:5. The tandem conjugate addition–alkylation also takes place in good yields. These reactions have been applied to the synthesis of enantiopure tetrahydropyrrolo[2,1- a ]isoquinolines.

Ring-closing metathesis reactions of dialkenyl amines, amides and carbamates catalyzed by Ru-catalysts provide efficient approaches to six-membered nitrogen heterocyclic compounds, which are precursors of a variety of natural products and related compounds.

In general perturbation methods starts with a known exact solution of a problem and add “small” variation terms in order to approach to a solution for a related problem without known exact solution. Perturbation theory has been widely used in almost all areas of science. Bhor’s quantum model, Heisenberg’s matrix mechanincs, Feyman diagrams, and Poincare’s chaos model or “butterfly effect” in complex systems are examples of perturbation theories. On the other hand, the study of Quantitative Structure-Property Relationships (QSPR) in molecular complex systems is an ideal area for the application of perturbation theory. There are several problems with exact experimental solutions (new chemical reactions, physicochemical properties, drug activity and distribution, metabolic networks, etc.) in public databases like CHEMBL. However, in all these cases, we have an even larger list of related problems without known solutions. We need to know the change in all these properties after a perturbation of initial boundary conditions. It means, when we test large sets of similar, but different, compounds and/or chemical reactions under the slightly different conditions (temperature, time, solvents, enzymes, assays, protein targets, tissues, partition systems, organisms, etc.). However, to the best of our knowledge, there is no QSPR general-purpose perturbation theory to solve this problem. In this work, firstly we review general aspects and applications of both perturbation theory and QSPR models. Secondly, we formulate a general-purpose perturbation theory for multiple-boundary QSPR problems. Last, we develop three new QSPR-Perturbation theory models. The first model classify correctly >100,000 pairs of intra-molecular carbolithiations with 75-95% of Accuracy (Ac), Sensitivity (Sn), and Specificity (Sp). The model predicts probabilities of variations in the yield and enantiomeric excess of reactions due to at least one perturbation in boundary conditions (solvent, temperature, temperature of addition, or time of reaction). The model also account for changes in chemical structure (connectivity structure and/or chirality paterns in substrate, product, electrophile agent, organolithium, and ligand of the asymmetric catalyst). The second model classifies more than 150,000 cases with 85-100% of Ac, Sn, and Sp. The data contains experimental shifts in up to 18 different pharmacological parameters determined in >3000 assays of ADMET (Absorption, Distribution, Metabolism, Elimination, and Toxicity) properties and/or interactions between 31723 drugs and 100 targets (metabolizing enzymes, drug transporters, or organisms). The third model classifies more than 260,000 cases of perturbations in the self-aggregation of drugs and surfactants to form micelles with Ac, Sn, and Sp of 94-95%. The model predicts changes in 8 physicochemical and/or thermodynamics output parameters (critic micelle concentration, aggregation number, degree of ionization, surface area, enthalpy, free energy, entropy, heat capacity) of self-aggregation due to perturbations. The perturbations refers to changes in initial temperature, solvent, salt, salt concentration, solvent, and/or structure of the anion or cation of more than 150 different drugs and surfactants. QSPR-Perturbation Theory models may be useful for multi-objective optimization of organic synthesis, physicochemical properties, biological activity, metabolism, and distribution profiles towards the design of new drugs, surfactants, asymmetric ligands for catalysts, and other materials.