Daniele Castagnolo

Synthesis, biological evaluation, and SAR study of novel pyrazole analogues as inhibitors of Mycobacterium tuberculosis: Part 2. Synthesis of rigid pyrazolones

Two series of novel rigid pyrazolone derivatives were synthesized and evaluated as inhibitors of Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis. Two of these compounds showed a high activity against MTB (MIC=4 microg/mL). The newly synthesized pyrazolones were also computationally investigated to analyze if their properties fit the pharmacophoric model for antitubercular compounds previously built by us. The results are in agreement with those reported by us previously for a class of pyrazole analogues and confirm the fundamental role of the p-chlorophenyl moiety at C4 in the antimycobacterial activity.

Synthesis, biological evaluation and SAR study of novel pyrazole analogues as inhibitors of Mycobacterium tuberculosis

As a continuation of our previous work that turned toward the identification of antimycobacterial compounds with innovative structures, two series of pyrazole derivatives were synthesized by parallel solution-phase synthesis and were assayed as inhibitors of Mycobacterium tuberculosis (MTB), which is the causative agent of tuberculosis. One of these compounds showed high activity against MTB (MIC = 4 microg/mL). The newly synthesized pyrazoles were also computationally investigated to analyze their fit properties to the pharmacophoric model for antitubercular compounds previously built by us and to refine structure-activity relationship analysis.

Synthesis and biological evaluation of new enantiomerically pure azole derivatives as inhibitors of Mycobacterium tuberculosis

A series of novel enantiomerically pure azole derivatives was synthesized. The new compounds, bearing both an imidazole as well as a triazole moiety, were evaluated as antimycobacterial agents. One of them proved to have activity against Mycobaterium tuberculosis comparable to those of the classical antibacterial/antifungal drugs Econazole and Clotrimazole.

Ligand-based virtual screening, parallel solution-phase and microwave-assisted synthesis as tools to identify and synthesize new inhibitors of mycobacterium tuberculosis.

In an attempt to identify new inhibitors of the growth of Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis, a procedure for the generation, design, and screening of a ligand‐based virtual library was applied. This used both an inu2005silico protocol centered on a recursive partitioning (RP) model described herein, and a pharmacophoric model for antitubercular agents previously generated by our research group. Two candidates emerged from databases of commercially available compounds, both characterized by a minimum inhibitory concentration (MIC) of 25u2005μgu2009mL−1. Based on these compounds, two series of derivatives were synthesized by both parallel solution‐phase and microwave‐assisted synthesis, leading to enhanced antimycobacterial activity. During both the design and synthesis, attention was focused on the efficient allocation of available resources with the aim of reducing the overall costs associated with calculation and synthesis.

Synthesis of new linear guanidines and macrocyclic amidinourea derivatives endowed with high antifungal activity against Candida spp. and Aspergillus spp.

New linear and cyclic guanidines were synthesized and tested in vitro for their antifungal activity toward clinically relevant strains of Candida species, in comparison to fluconazole. Macrocyclic compounds showed a minimum inhibitory concentration in the micromolar range and a biological activity profile in some cases better than that of fluconazole. One macrocyclic derivative was also tested against Aspergillus species and showed high antifungal activity comparable to that of amphotericin B and itraconazole.

Discovery and synthesis of novel benzofurazan derivatives as inhibitors of influenza A virus.

The identification of a novel hit compound inhibitor of the protein-protein interaction between the influenza RNA-polymerase PA and PB1 subunits has been accomplished by means of high-throughput screening. A small family of structurally related molecules has been synthesized and biologically evaluated with most of the compounds showing micromolar potency of inhibition against viral replication.

The fight against the influenza A virus H1N1: Synthesis, molecular modeling, and biological evaluation of benzofurazan derivatives as viral RNA polymerase inhibitors

The influenza RNA polymerase complex, which consists of the three subunits PA, PB1, and PB2, is a promising target for the development of new antiviral drugs. A large library of benzofurazan compounds was synthesized and assayed against influenza virus A/WSN/33 (H1N1). Most of the new derivatives were found to act by inhibiting the viral RNA polymerase complex through disruption of the complex formed between subunits PA and PB1. Docking studies were also performed to elucidate the binding mode of benzofurazans within the PB1 binding site in PA and to identify amino acids involved in their mechanism of action. The predicted binding pose is fully consistent with the biological data and lays the foundation for the rational development of more effective PA–PB1 inhibitors.

Synthesis, Biological Activity, and ADME Properties of Novel S-DABOs/N-DABOs as HIV Reverse Transcriptase Inhibitors

Previous studies aimed at exploring the SAR of C2‐functionalized S‐DABOs demonstrated that the substituent at this position plays a key role in the inhibition of both wild‐type RT and drug‐resistant enzymes, particularly the K103N mutant form. The introduction of a cyclopropyl group led us to the discovery of a potent inhibitor with picomolar activity against wild‐type RT and nanomolar activity against many key mutant forms such as K103N. Despite its excellent antiviral profile, this compound suffers from a suboptimal ADME profile typical of many S‐DABO analogues, but it could, however, represent a promising candidate as an anti‐HIV microbicide. In the present work, a new series of S‐DABO/N‐DABO derivatives were synthesized to obtain additional SAR information on the C2‐position and in particular to improve ADME properties while maintaining a good activity profile against HIV‐1 RT. Inu2005vitro ADME properties (PAMPA permeation, water solubility, and metabolic stability) were also experimentally evaluated for the most interesting compounds to obtain a reliable indication of their plasma levels after oral administration.

Stereoselective protecting group free synthesis of D,L-gulose ethyl glycoside via multicomponent enyne cross metathesis―hetero Diels―Alder reaction

An efficient and stereoselective synthesis of D,L-gulose was described. The key step of the synthetic route is represented by a multicomponent enyne cross metathesis-hetero Diels-Alder reaction which allows the formation of the pyran ring from cheap and commercially available substrates in a single synthetic step. The synthesis of D,L-gulose was accomplished without the use of protecting groups making this approach highly desirable also in terms of atom economy.

Antioxidant properties of propargylamine derivatives: assessment of their ability to scavenge peroxynitrite.

A series of arylpropargylamines, variously substituted in the hydrogen in p‐position and in the propargyl moiety, were studied as potential peroxynitrite scavengers. The scavenging activity of these compounds was evaluated through peroxynitrite (ONOO−)‐mediated oxidation of dichlorofluorescin and linoleic acid by measuring the dichlorofluorescein formation and oxygen consumption, respectively. Among tested compounds, only 1‐phenylpropargylamine (AP3) promoted concentration‐dependent inhibition of ONOO−‐induced dichlorofluorescin and linoleic acid oxidation with IC50 values of 637 and 63 μm, respectively. The AP3 spectral changes in UV‐visible absorbance properties in the presence of peroxynitrite suggested the formation of a new compound. This was identified by gas‐chromatograph‐mass spectrometer analysis as phenylpropargyl alcohol. Structure—activity relationship analysis indicated that the scavenging activity of AP3 was due to the aminopropargyl moiety and availability of the nitrogen electron pair. This data suggested that AP3 could be considered a lead compound for the synthesis of new ONOO− scavenger derivatives.