New Chromane-Based Derivatives as Inhibitors of Mycobacterium tuberculosis Salicylate Synthase (MbtI): Preliminary Biological Evaluation and Molecular Modeling Studies

Tuberculosis is the leading cause of death from a single infectious agent worldwide; therefore, the need for new antitubercular drugs is desperate. The recently validated target salicylate synthase MbtI is the first enzyme involved in the biosynthesis of mycobactins, compounds able to chelate iron, an essential cofactor for the survival of Mycobacterium tuberculosis in the host. Here, we report on the synthesis and biological evaluation of chromane-based compounds as new potential inhibitors of MbtI. Our approach successfully allowed the identification of a novel lead compound (1), endowed with a promising activity against this enzyme (IC50 = 55 μM). Molecular modeling studies were performed in order to evaluate the binding mode of 1 and rationalize the preliminary structure-activity relationships, thus providing crucial information to carry out further optimization studies

Discovery and development of novel salicylate synthase (MbtI) furanic inhibitors as antitubercular agents

We report on the virtual screening, synthesis, and biological evaluation of new furan derivatives targeting Mycobacterium tuberculosis salicylate synthase (MbtI). A receptor-based virtual screening procedure was applied to screen the Enamine database, identifying two compounds, I and III, endowed with a good enzyme inhibitory activity. Considering the most active compound I as starting point for the development of novel MbtI inhibitors, we obtained new derivatives based on the furan scaffold. Among the SAR performed on this class, compound 1a emerged as the most potent MbtI inhibitor reported to date (Ki = 5.3 μM). Moreover, compound 1a showed a promising antimycobacterial activity (MIC99 = 156 μM), which is conceivably related to mycobactin biosynthesis inhibition

Special Issue: Frontiers in Antimicrobial Drug Discovery and Design

Since the discovery of Penicillin, antibiotics have saved millions of lives every year.[...

Ten years of medicinal chemistry (2005-2014) in the journal of medicinal chemistry: Country of contributors, topics, and public-private partnerships miniperspective

This review analyzes the articles that have appeared during the past 10 years in the Journal of Medicinal Chemistry, the leading journal in the field of medicinal chemistry, to provide a picture of the changing trends in this research area. Our analysis involved the country of the corresponding author, assuming that he/she was the leader of the research group, the interaction between private and public sectors, and the research topics. This analysis provides information on the contributions to the journal of authors from each country and highlights the differences between the public and private sectors regarding the research topics pursued. Moreover, changes in the number of articles that describe work on hits, leads, or clinical candidates during these years have been correlated with the affiliation of the contributors (public or private). An analysis of top-cited articles that have appeared in the journal has also been included. The data will provide the basis for understanding the evolution that is taking place in medicinal chemistry

New perspectives on the development of antiobesity drugs

After many years of research, obesity is still a disease with an unmet medical need. Very few compounds have been approved, acting mainly on neuromediators; researches, in recent years, pointed toward compounds potentially safer than first-generation antiobesity drugs, able to interact with one or more (multitarget therapy) receptors for substances produced by the gut, adipose tissue and other targets outside CNS. Other holistic approaches, such as those involving gut microbiota and plant extracts, appeared recently in the literature, and undoubtedly will contribute to the discovery of a valuable therapy for this disease. This review deals with the positive results and the pitfalls obtained following these approaches, with a view on their clinical trial studies

Designing Approaches to Multitarget Drugs

Plexxikon adopted a fragment-based drug discovery strategy for the design of multitarget drugs that represents an evolution of the procedure followed for the discovery of a family of selective phosphodiesterase (PDE) inhibitors. The fragment-based drug design was successfully applied for the discovery of multitarget protein-protein interaction inhibitors. Moreover, protein-protein interactions do not have natural small molecule partners, not allowing the design of compounds on the basis of the structure of a small natural substrate or ligand. The modern phenotypic screening has been successfully applied for the discovery of antinociceptive multitarget compounds and for RET inhibitors; this kind of approach can be used fruitfully also for drug repurposing. A survey of the literature showed that the most common strategy followed for the design of multitarget drugs is that based on the use of pharmacophores or structure-activity relationship (SAR) around a lead

Laboratorio di Preparazione Estrattiva e Sintetica dei Farmaci

Questo testo si propone di fornire le conoscenze per eseguire praticamente la sintesi di un prodotto (v. Figura) o la sua estrazione da materiale vegetale. Per realizzare questi processi occorre familiarizzarsi con varie metodiche generali, che andranno poi applicate ai singoli casi in base a ragionamenti appropriati. Il testo è stato calibrato in modo da soddisfare le esigenze di un Corso di Laboratorio di Preparazione Estrattiva e Sintetica dei Farmaci per il Corso di Laurea in Chimica e Tecnologia Farmaceutiche, in cui la parte pratica è svolta contemporaneamente alla parte teorica, e le conoscenze pratiche (“di laboratorio”) dello studente sono limitate. Esistono banche dati (ad esempio SciFinder) che possono indirizzare a pubblicazioni che contengono la via di sintesi di un composto noto, oppure possono suggerire una strategia di sintesi di composti non noti, ma sono solo il giudizio e l’esperienza individuali che hanno l’ultima parola, specialmente quando si tratta di sintetizzare o estrarre un prodotto ignoto (il caso più comune per chi fa ricerca). Vari parametri (scala, disponibilità e prezzo dei prodotti di partenza, difficoltà di esecuzione della sintesi e rese attese) sono in grado di influenzare le strategie sintetiche e verranno quindi presi in considerazione per la scelta della via di sintesi. Il presente libro si occupa inizialmente, sia da un punto di vista teorico che pratico, di tecniche generali; quindi si passa alla descrizione ed esecuzione in laboratorio di sintesi di composti di interesse farmaceutico. In particolare, verranno illustrati casi in cui l’ordine di aggiunta dei reattivi, la stechiometria o la presenza di altri composti (iniziatori, ecc.) possono modificare l’andamento di una reazione. Accanto alla procedura “classica” di sintesi, in cui si fa avvenire la reazione tra i composti A e B in un contenitore (pallone, reattore) per ottenere il prodotto C (sintesi in serie), verranno illustrate strategie innovative (Flow Chemistry) in cui la reazione viene condotta in tubi sottili, dove i reagenti fluiscono in continuo (v. Figura). Per finire, verranno riportate tecniche di sintesi in parallelo (generazione di librerie di composti) in soluzione o in fase solida, e reazioni di bioconiugazione