Improving the Potency of N-Aryl-2,5-dimethylpyrroles against Multidrug-Resistant and Intracellular Mycobacteria

A series of N-phenyl-2,5-dimethylpyrrole derivatives, designed as hybrids of the antitubercular agents BM212 and SQ109, have been synthesized and evaluated against susceptible and drug-resistant mycobacteria strains. Compound 5d, bearing a cyclohexylmethylene side chain, showed high potency against M. tuberculosis including MDR-TB strains at submicromolar concentrations. The new compound shows bacteriostatic activity and low toxicity and proved to be effective against intracellular mycobacteria too, showing an activity profile similar to isoniazid

Directed Evolution of an Artificial Imine Reductase

Artificial metalloenzymes, resulting from incorporation of a metal cofactor within a host protein, have received increasing attention in the last decade. The directed evolution is presented of an artificial transfer hydrogenase (ATHase) based on the biotin-streptavidin technology using a straightforward procedure allowing screening in cell-free extracts. Two streptavidin isoforms were yielded with improved catalytic activity and selectivity for the reduction of cyclic imines. The evolved ATHases were stable under biphasic catalytic conditions. The X-ray structure analysis reveals that introducing bulky residues within the active site results in flexibility changes of the cofactor, thus increasing exposure of the metal to the protein surface and leading to a reversal of enantioselectivity. This hypothesis was confirmed by a multiscale approach based mostly on molecular dynamics and protein-ligand dockings

Tackling the antibiotic resistance in tuberculosis: Synthesis and biological evaluation of novel antitubercular agents and development of novel methodologies for the synthesis of heterocycles

Mycobacterium tuberculosis (Mtb), the etiological agent of Tuberculosis (TB) is developing new multi drug-resistant (MDR) and extensively drug-resistant (XDR) strains to the current drugs used in therapy. Of particular concern the wide spreading of tuberculosis, the high rate of development of resistance, and the high mortality of the patients due to the lack of effective therapy against TB infections. In order to face this problem, two series of novel compounds were designed, synthesised and evaluated against a panel of mycobacterial strains. The first series of compounds includes analogues of the third line drug thioridazine (TZ). TZ is a known antipsychotic drug belonging to the phenothiazine drug group, which showed good activity against MDR-TB infections but causes severe side effects which limit its use in therapy. Among the first series of compounds, five new compounds showed anti-tubercular activity similar or higher than TZ. Moreover, two derivatives showed potent inhibition towards the whole-cell drug efflux pump activity of mycobacteria comparable to that of verapamil, and turning to be promising multi-drug resistance reversal agents. A second series of compounds consist of small molecules which have originally been designed as hybrids of the anti-tubercular drugs BM212 and SQ109. Computational studies revealed a perfect superposition of the structures of SQ109 and BM212 and showed that the two drugs share common features. Five of the resulting compounds showed micromolar anti-tubercular activity on pathogenic TB. Two of them proved to be highly active also against multi-drug resistant clinical isolates and one of these also showed minimal eukaryotic cell toxicity, and therefore would be an excellent lead candidate for preclinical trials. In parallel to the identification of novel compounds active against mycobacteria, new synthetic methodologies for the synthesis of antitubercular heterocyclic scaffolds have been developed. In particular two approaches for the synthesis of pyrrole compounds were developed. Both procedures involve an olefin or enyne metathesis reaction as a key step. The first approach involves the synthesis of 1,2,3-substituted pyrroles, through a tandem enyne cross metathesis-cyclization reaction of propargylamines with ethyl-vinyl ether. The reaction is rapid, procedurally simple and represents a facile entry to the synthetically challenging 4,5-unsubstituted pyrroles. The second methodology allows the synthesis of substituted pyrroles from diallyl-amines via a chemo-enzymatic cascade based on the combination of olefin metathesis together with monoamine oxidase (MAO) biocatalysts. These reactions were carried out in aqueous media and mild temperature leading to the formation of substituted pyrroles in a single step and in high yields

Unveiling the Biocatalytic Aromatizing Activity of Monoamine Oxidases MAO-N and 6-HDNO:Development of Chemoenzymatic Cascades for the Synthesis of Pyrroles

A chemoenzymatic cascade process for the sustainable production of pyrroles has been developed. Pyrroles were synthesized by exploiting the previously unexplored aromatizing activity of monoamine oxidase enzymes (MAO-N and 6-HDNO). MAO-N/6-HDNO whole cell biocatalysts are able to convert 3-pyrrolines into pyrroles under mild conditions and in high yields. Moreover, MAO-N can work in combination with the ruthenium Grubbs catalyst, leading to the synthesis of pyrroles from diallylamines/-anilines in a one-pot cascade metathesis–aromatization sequence

Microwave-assisted domino reactions of propargylamines with isothiocyanates: selective synthesis of 2-aminothiazoles and 2-amino-4-methylenethiazolines

A simple and versatile microwave-assisted protocol for the synthesis of 2-aminothiazoles has been developed. The domino reaction of propargylamines and isothiocyanates in the presence of catalytic PTSA leads to the selective synthesis of 2-aminothiazoles at temperatures above 130 °C and in a few minutes. The same reaction carried out at lower temperatures leads to the formation of the tautomeric 2-amino-4-methylenethiazolines

Synthesis and Reactivity of Propargylamines in Organic Chemistry

Propargylamines are a versatile class of compounds which find broad application in many fields of chemistry. This review aims to describe the different strategies developed so far for the synthesis of propargylamines and their derivatives as well as to highlight their reactivity and use as building blocks in the synthesis of chemically relevant organic compounds. In the first part of the review, the different synthetic approaches to synthesize propargylamines, such as A3 couplings and C-H functionalization of alkynes, have been described and organized on the basis of the catalysts employed in the syntheses. Both racemic and enantioselective approaches have been reported. In the second part, an overview of the transformations of propargylamines into heterocyclic compounds such as pyrroles, pyridines, thiazoles, and oxazoles, as well as other relevant organic derivatives, is presented.</p

Synthesis of 1,2,3-substituted pyrroles from propargylamines via a one-pot tandem enyne cross metathesis-cyclization reaction

Enyne cross metathesis of propargylamines with ethyl vinyl ether enables the one-pot synthesis of substituted pyrroles. A series of substituted pyrroles, bearing alkyl, aryl, and heteroaryl substituents, has been synthesized in good yields under microwave irradiation. The reactions are rapid and procedurally simple and also represent a facile entry to the synthetically challenging 1,2,3-substituted pyrroles. The value of the methodology is further corroborated by the conversion of pyrroles into 3-methyl-pyrrolines and the derivatization of the 3-methyl-substituent arising from the metathesis reaction

Magnesium profile in autism.

The aim of the present study was to determine and compare plasma and erythrocyte concentrations of magnesium in 12 autistic children (10 boys, 2 girls), 17 children with other autistic spectrum disorders (14 boys, 3 girls), 5 girls with classic Rett syndrome, and 14 normal children (7 boys, 7 girls) of the same age. No differences in intracellular Mg were found between controls and pathological subjects; however, autistic children and children with other autistic spectrum disorders had significantly lower plasma concentrations of Mg than normal subjects (p=0.013 and p=0.02, respectively). Although our study population was small, we conclude that children with autistic spectrum disorders require special dietary management. If these cases are diagnosed at an early stage, they can be helped through diet