Rossella Fioravanti

Chalcones: A valid scaffold for monoamine oxidases inhibitors

A large series of substituted chalcones have been synthesized and tested in vitro for their ability to inhibit human monoamine oxidases A and B (hMAO-A and hMAO-B). While all the compounds showed hMAO-B selective activity in the micro- and nanomolar ranges, the best results were obtained in the presence of chlorine and hydroxyl or methoxyl substituents. To better understand the enzyme-inhibitor interaction and to explain the selectivity of the most active compounds toward hMAO-B, molecular modeling studies were carried out on new, high resolution, hMAO-B crystallographic structures. For the only compound that also showed activity against hMAO-A as well as low selectivity, the molecular modeling study was also performed on the hMAO-A crystallographic structure. The docking technique provided new insight on the inhibition mechanism and the rational drug design of more potent/selective hMAO inhibitors based on the chalcone scaffold.

Homoisoflavonoids: Natural Scaffolds with Potent and Selective Monoamine Oxidase-B Inhibition Properties

A series of homoisoflavonoids [(E)-3-benzylidenechroman-4-ones 1a-w, 3-benzyl-4H-chromen-4-ones 2a-g, and 3-benzylchroman-4-ones 3a-e] have been synthesized and tested in vitro as inhibitors of human monoamine oxidase isoforms A and B (hMAO-A and hMAO-B). Most of the compounds were found to be potent and selective MAO-B inhibitors. In general, the (E)-3-benzylidenechroman-4-ones 1a-w showed activities in the nano- or micromolar range coupled with high selectivity against hMAO-B. The reduction of the exocyclic double bond results in compounds 3a-e selective against isoform B and active in the micromolar range. In contrast, the endocyclic migration of the double bond (compounds 2a-g) generally produces the loss of the inhibitory activity or a marked reduction in potency. (E)-3-(4-(Dimethylamino)benzylidene)chroman-4-one (1l) and (E)-5,7-dihydroxy-3-(4-hydroxybenzylidene)chroman-4-one (1h) were the most interesting compounds of the entire series of inhibitors, showing hMAO-B affinity better than the selective inhibitor selegiline. Molecular modeling studies have been carried out to explain the selectivity of the most active homoisoflavonoids 1h and 1l.

Synthesis and biological evaluation of N-substituted-3,5-diphenyl-2-pyrazoline derivatives as cyclooxygenase (COX-2) inhibitors

Eighteen new 1-N-substituted-3,5-diphenyl-2-pyrazoline derivatives have been synthesized and cyclooxygenase (COX-1 and COX-2) inhibitory activities have been evaluated. The results of these biological assays showed that all of new derivatives are not endowed with improved anti-inflammatory activity against COX-1, but some of them showed a good activity against COX-2. To evaluate the binding mode of the most significative compounds (2d, 2f, 2g and 2k) docking studies were carried out. These studies confirmed biological data, in fact these compounds were able to fit into the active site of COX-2.

A new series of flavones, thioflavones, and flavanones as selective monoamine oxidase-B inhibitors.

A new series of synthetic flavones, thioflavones, and flavanones has been synthesized and evaluated as potential inhibitors of monoamine oxidase isoforms (MAO-A and -B). The most active series is the flavanone one with higher selective inhibitory activity against MAO-B. Some of these flavanones (mainly the most effective) have been separated and tested as single enantiomers. In order to investigate the MAOs recognition of the most active and selective compounds, a molecular modeling study has been performed using available Protein Data Bank (PDB) structures as receptor models for docking experiments.

New pyrrole derivatives as antimycobacterial agents analogs of BM212

During the course of our investigations in the field of azole antimicrobial agents, we have identified BM212 a pyrrole derivative with good in vitro activity against mycobacteria and candidae. These findings prompted us to prepare new pyrrole derivatives 2-6 in the hope of increasing the activity. The microbiological data showed interesting in vitro activity against Mycobacterium tuberculosis and atypical mycobacteria.

Synthesis, molecular modeling studies and selective inhibitory activity against MAO of N1-propanoyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives

A series of N1-propanoyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives were synthesized and assayed as inhibitors of MAO-A and MAO-B isoforms. Most of the tested compounds showed inhibitory activity with micromolar values and MAO-A selectivity. In addition a computational work was carried out on the most selective compound 3b to highlight the most relevant interactions in the mechanism of recognition within both the MAO-A and the MAO-B enzyme active sites.

Focusing on new monoamine oxidase inhibitors

Importance of the field: Monoamine oxidase (MAO) plays a significant role in the control of intracellular concentration of monoaminergic neurotransmitters or neuromodulators and dietary amines. The rapid degradation of these molecules ensures the proper functioning of synaptic neurotransmission and is critically important for the regulation of emotional and other brain functions. Furthermore, modulators of neurotransmitters exert pleiotropic effects on mental and cognitive functions. The by-products of MAO-mediated reactions include several chemical species with neurotoxic potential. It is widely speculated that prolonged or excessive activity of these enzymes may be conducive to mitochondrial damages and neurodegenerative disturbances. In keeping with these premises, the development of human MAO inhibitors has led to important breakthroughs in the therapy of several neuropsychiatric disorders. Areas covered in this review: This review highlights the recent MAO inhibitors related patents published from July 2005 to December 2009. It also reports on new associations of already known MAO inhibitors with other drugs, innovative therapeutic targets, MAO inhibitors obtained by plants extraction, alternative administration routes and synthetic processes. What the reader will gain: The reader will gain an overview of the main structures being investigated and their biological activities. Take home message: Several of these MAO inhibitors appear promising for further clinical development.

Research on antibacterial and antifungal agents. XI: Synthesis and antimicrobial activity of N-heteroaryl benzylamines and their Schiff bases

Summary The synthesis and antimicrobial activity of new N -heteroaryl benzylamines and their Schiff bases are reported. Antifungal data were compared with those obtained with miconazole, ketoconazole, enilconazole and imazalil sulfate, which showed that some of the tested compounds possessed moderate activity against strains of Candida albicans , Candida sp and good activity against isolates of plant pathogenic fungi. In contrast the synthesized compounds showed poor antibacterial activity, except for 3j which exhibited a better activity than nalidixic acid used as positive control. The results obtained are discussed on the basis of structure-activity relationships.

Recent development of monoamine oxidase inhibitors

The monoamine oxidases (MAO-A and MAO-B) are flavoenzymes located in the outer mitochondrial membrane responsible for the oxidative deamination of many endogenous and exogenous monoamines. Recognition of the importance of monoamine oxidases as targets for drug intervention for the treatment of a variety of conditions, such as schizophrenia, Alzheimer’s disease, Parkinson’s disease and other psychiatric and neurological disorders, has produced an enormous interest in the development of molecules that act as inhibitors on these enzymes. This review mainly focuses on the numerous monoamine oxidase inhibitor (MAO-I)-related patents published from August 2002 to June 2005. In this paper recent developments of monoamine oxidase inhibitors are reported, ordering all patents by molecular structure. A structure–activity relationship (SAR) study that reports on known MAO inhibitors is also outlined before a discussion on new associations with other drugs of classical MAO inhibitors and their new target.

Building a pharmacophore model for a novel class of antitubercular compounds

Starting from a set of 32 antitubercular compounds, for the first time a three-dimensional pharmacophore model has been derived through a computational approach based on CATALYST software. The model proved to be able to identify compounds belonging to classes of molecules already reported as antitubercular agents.