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Tuberculosis is one of the top 10 causes of death worldwide and the leading cause of death from a single infectious agent, mainly due to Mycobacterium tuberculosis (MTB). Recently, clinical prognoses have worsened due to the emergence of multi-drug resistant (MDR) and extensive-drug resistant (XDR) tuberculosis, which lead to the need for new, efficient and safe drugs. Among the several strategies, polypharmacology could be considered one of the best solutions, in particular, the multitarget directed ligands strategy (MTDLs), based on the synthesis of hybrid ligands acting against two targets of the pathogen. The framework strategy comprises linking, fusing and merging approaches to develop new chemical entities. With these premises, this review aims to provide an overview of the recent hybridization approach, in medicinal chemistry, of the most recent and promising multitargeting antimycobacterial candidates.

Background: Mycobacterium Tuberculosis (Mtb) is the causative pathogen of Tuberculosis (TB) and outbreaks are more common among immunosuppressed persons infected with HIV. The current treatment regimens are lengthy and toxic, yet the therapy has remained unchanged for many decades, so there is a need to find new structures with selective mechanism of action. Moreover, the increased incidence of severe disseminated infections produced by undiagnosed Multidrug-resistant (MDR), worsen clinical treatment and contribute the spread of the disease. Objective: The aim of our study was to evaluate the potential of imidazole and triazole moieties for antimycobacterial activity, by synthesizing some 1-(1-(aryl)-2-(2,6-dichlorophenyl)hydrazono)ethyl- 1H-imidazole and 1H-1,2,4-triazole derivatives 2a-l. Methods: The title compounds were obtained via classical organic synthesis. The antimicrobial activity was evaluated using the method of microdilution and the cytotoxicity assay was performed by MTT method. Results: The results indicated that the presence of both the imidazole ring and that of the 2,6- dichlorosubstituted phenyl moiety, is more relevant for inhibitory activity against Mtb than the triazole nucleus and the unsubstituted phenyl ring. Among the series, (E)-1-(2-(5-chlorothiophen-2-yl)-2-(2- (2,6-dichlorophenyl)hydrazono)ethyl)-1H-imidazole derivative 2f and (Z)-1-(2-([1,1’-biphenyl]-4-yl)- 2-(2-(2,6-dichlorophenyl)hydrazono)ethyl]-1H-imidazole derivatives 2e exhibited a promising antimycobacterial property and the latter also displayed a safe cytotoxic profile. Conclusion: The synthesized compounds were studied for their antitubercular activity. Among the series, the compounds 2e and 2f appeared to be the most promising agents and, according to the docking assessment, the compounds could be CYP51 inhibitors. These evidences could be useful for the future development of new antimycobacterial derivatives targeting CYP51 with more specificity for the mycobacterial cell enzyme.

Originally considered an enigmatic polypeptide, the σ1receptor has recently been identified as a unique ligand-regulated protein. Many studies have shown the potential of σ1receptor ligands for the treatment of various diseases of the central nervous system (CNS); nevertheless, almost no information about the 3D structure of the receptor and/or the possible modes of interaction of the σ1protein with its ligands have been unveiled so far. With the present work we validated our σ13D homology model and assessed its reliability as a platform for σ1ligand structure-based drug design. To this purpose, the 3D σ1model was exploited in the design of 33 new σ1ligands and in their ranking for receptor affinity by extensive molecular dynamics simulation-based free energy calculations. Also, the main interactions involved in receptor/ligand binding were analyzed by applying a per residue free energy deconvolution and in silicoalanine scanning mutagenesis calculations. Subsequently, all compounds were synthesized in our laboratory and tested for σ1binding activity in vitro. The agreement between in silicoand in vitroresults confirms the reliability of the proposed σ13D model in the a prioriprediction of the affinity of new σ1ligands. Moreover, it also supports and corroborates the currently available biochemical data concerning the σ1protein residues considered essential for σ1ligand binding and activity.

Objectives: To synthesize new antimycobacterial and antifungal drugs that act by binding to sterol 14α-demethylase (14DM) and to characterize the drug–target protein interactions using computer-based molecular simulations.Methods: Different series of imidazole and triazole derivatives having an azomethine linkage to pyridine 2-carboxamidrazone were designed and synthesized. Molecular dynamic simulations of the sterol 14DM (a mixed-function oxidase involved in sterol synthesis in eukaryotic and prokaryotic organisms) complexed with new azole derivatives have been performed to both qualify and quantify the protein–ligand interactions. MICs of the compounds were evaluated by reference assay and by the recently developed Microdilution Resazurin Assay (MRA).Results: Halogenated derivatives showed good activity, with an MIC90 of 1 mg/L against 33 Candida spp. clinical strains; most compounds also had inhibitory activity against Mycobacterium tuberculosis reference and clinical strains, with MICs in the range 4–64 mg/L. Molecular modelling investigations showed that the active new compounds may interact at the active site of both the fungal and the mycobacterial cytochrome P450-dependent sterol-14α-demethylase and that the calculated binding free energy values are in agreement with the corresponding MIC values.Conclusions: The combined experimental and computational approach can be helpful in targeted drug design, thus yielding valuable information for the synthesis and prediction of activity of a second generation of inhibitors.

We describe the preparation of racemic N,N‐dimethyl‐3‐(naphthalen‐2‐yl)‐butan‐1‐amines, potential sigma1 ligands, and their resolution via chiral HPLC. In order to obtain enantiopure compounds, direct chromatographic methods of separation using chiral stationary phases were investigated. Different methods suitable for both analytical and semipreparative purposes are proposed. The best resolutions were achieved using cellulose tris (3,5‐dimethylphenyl carbamate) (Chiralcel OD and OD‐H) and amylose tris (3,5‐dimethylphenyl carbamate) (Chiralpak AD). On the basis of the preliminary chromatographic results, the resolution of compound 1 was transferred onto a Chiralcel OD semipreparative column. The enantiomers were obtained in high enantiomeric excess. The configurational assignment was performed by circular dichroism. Computational analysis was used to explore the enantioselective recognition process of compound 1 with the Chiralcel OD stationary phase. Chirality, 2006. © 2006 Wiley‐Liss, Inc.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

For Abstract see ChemInform Abstract in Full Text.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.