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Menaquinone is an essential component of the electron transport chain in many pathogens and consequently enzymes in the menaquinone biosynthesis pathway are potential drug targets for the development of novel antibacterial agents. Few years ago, Li et al.1 identified several 1,4-benzoxazine-2-one derivatives, that target MenB (1,4-dihydroxy-2-naphtoyl-CoA synthase), endowed with high antibacterial activity against Mycobacteria tuberculosis H37Rv with MIC values as low as 0.6 μg/ml. By these assumptions we designed and synthesized the corresponding isosters 1,4-benzoxazin-3-one derivatives in order to investigate the SAR of these novel compounds in comparision with the lead and with the purpose to improve the antimycobacterial activity also towards MOTT (Mycobacteria Other Than Tuberculosis) strains. Menaquinone is an essential component of the electron transport chain in many pathogens and consequently enzymes in the menaquinone biosynthesis pathway are potential drug targets for the development of novel antibacterial agents. Few years ago, Li et al.1 identified several 1,4-benzoxazine-2-one derivatives, that target MenB (1,4-dihydroxy-2-naphtoyl-CoA synthase), endowed with high antibacterial activity against Mycobacteria tuberculosis H37Rv with MIC values as low as 0.6 μg/ml. By these assumptions we designed and synthesized the corresponding isosters 1,4-benzoxazin-3-one derivatives in order to investigate the SAR of these novel compounds in comparision with the lead and with the purpose to improve the antimycobacterial activity also towards MOTT (Mycobacteria Other Than Tuberculosis) strains. Figure 1. Optimization of lead compound To date, the antimycobacterial activity is under investigation.

To date, the research in the field of sigma receptors (sR) still remains difficult, considering the fact that only the s1 subtype was purified and cloned from several animal species including man, while the s2R subtype has not been cloned yet and still remains an unknown protein. Is well-known that s1R has been associated with many diseases including stroke, cocaine addiction, pain, cancer, and neurodegenerative pathologies1 while s2R subtype are overexpressed in several tumor cells. By these considerations the s1 ligands could be used as neuroprotective agents, while s2 ligands can be considered a tool for cancer therapy and diagnosis (as PET or SPECT). Starting from the structure of previously reported2, high-affinity benzoxazolone-based s1 ligands, the three-dimensional homology model of the s1R was exploited for retrieving the molecular determinants to fulfill the optimal pharmacophore requirements. Accordingly, the benzoxazolone moiety was replaced by other heterocyclic scaffolds, the relevant conformational space in the s1R binding cavity was explored, and the effect on s1R binding affinity was ultimately assessed. Next, the compounds designed in silico were synthesized, and their affinity and selectivity toward s1 and s2 receptors were tested. We designed and synthesized two new series of compounds 1a-h and 2a-h as potential sigma ligands. The highest s1 affinity (Ki= 16nM) was reached by compound 1a (R=H; R’= CH3); towards s2R the best result was obtained by derivative 2h (R= 2,4(CH3)2; R’= cyclohexyl), with a Ki value of 80 nM.

On the basis of some benzo[d]oxazol-2(3H)-one derivatives previously developed by us and gifted with excellent σ1 affinity and selectivity, we have synthesized a new series of compounds 1 and 2, changing the benzoxazolone moiety with similar groups to evaluate their effects toward the sigma affinity and selectivity. With the aim to discover some new sigma 2 ligands, we try to modulate the selectivity and the affinity of the compounds towards the two receptor subtypes changing the middle piperidinemethyl spacer (1a-j) with a less constrained butylaminomethyl chain (2 a-j). A preliminarly binding study (Discovery studio 2.5) of the p-fluoro derivatives of both series confirm the interactions between the structure of our new derivatives and the features of the σ1 3D-receptor model (Fig.1). Furthermore an initial binding test was performed for the compound 1d (p-F) which gave Ki values of 67 nM and 286 nM for σ1 and σ2 respectively. The evaluation on the complete series is still in progress.

Originally considered an enigmatic receptor, the sigma1 receptor has recently been identified as a unique ligand-regulated protein. Since its discovery, many studies have shown the potential of sigma1 receptor ligands for the treatment of various diseases of the central nervous system (CNS). However, to date almost no information are available not only the interaction of ligands but also the differences in the interactions of agonists and antagonists with the sigma1 receptor protein have not yet been determined. Under these gloomy perspectives, in this work we embarked in the following, very ambitious task: we i) designed and synthesized novel ligands with high affinity and selectivity for the 1 receptor protein based on our unique in-house developed 3D model of the receptor, and a combination of 3D pharmacophore-based docking (Figure1) and MM/PBSA free energy of binding scoring (1); ii) determined the sigma1 affinity of the ligands in receptor binding studies with radioligands; iii) parallel in silico and experimental site directed mutagenesis experiments yielded a preliminary molecular-based rationale for the agonistic and antagonistic effects of the ligands; These results afforded a dramatic improvement in the understanding of the functions and roles of the sigma1 receptor. This, in turn, will foster the development of news drugs aimed at treating frequent and important human illness such as Alzheimer’s disease, depression, anxiety and pain.

Lo scopo di questo testo è quello di fornire un manuale di facile consultazione per tutti gli studenti dei corsi di laurea in Farmacia e in Chimica e Tecnologia Farmaceutiche, che frequentano un corso di analisi organica e/o inorganica qualitativa di sostanze farmaceutiche. Il manuale è ulteriormente rivolto a tutti coloro che hanno necessità di una guida che indirizzi in modo sistematico ad una rapida separazione di miscele e identificazione delle singole componenti senza l’ausilio di particolari tecniche strumentali. Questo, per esempio, è il caso dell’espletamento della prova di riconoscimento di farmaci incogniti prevista dall’esame di stato per l’abilitazione alla professione di farmacista. L’impostazione seguita nella stesura del testo è di tipo tradizionale. L’obiettivo principale del libro è quello di guidare il lettore attraverso un percorso analitico sistematico che, mediante una serie di operazioni sequenziali, consenta di riconoscere da prima la classe di appartenenza del farmaco incognito e successivamente la sua identificazione. La prima parte del testo illustra i principi chimici e fisici nonché tutte le operazioni pratiche e le apparecchiature più comunemente utilizzate per isolare un composto puro da una miscela (o miscuglio). Le tecniche descritte in questa parte del testo sono: estrazione con solvente, cristallizzazione, distillazione, cromatografia, evaporazione, filtrazione e centrifugazione.

This study presents for the first time the 3D model of the σ1 receptor protein as obtained from homology modeling techniques, shows the applicability of this structure to docking-based virtual screening, defines a computational strategy to optimize the results based on a combination of 3D pharmacophore-based docking and MM/PBSA free energy of binding scoring, and provides evidence that these in silico models and recipes are powerful tools on which virtual screening of new σ1 ligands can be based. In particular, the validation of the applicability of docking-based virtual screening to homology models is of utmost importance, since no crystal structure is available to date for the σ1 receptor, and this missing information still constitutes a major hurdle for a rational ligand design for this important protein target.

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Search of new antifungal compounds was performed through a preliminary computer modeling of drug/enzymecomplexes. All compounds have been tested against a strain of Candida Albicans 3038 and a strain of Mycobacterium tuberculosis H37Rv to evaluate the antifungal and the antimycobacterial activity respectively.