Daniela De Vita

Synthesis and antifungal activity of a new series of 2-(1H-imidazol-1-yl)- 1-phenylethanol derivatives

A new series of aromatic ester and carbamate derivatives of 2-(1H-imidazol-1-yl)-1-phenylethanol were synthesized and evaluated for their antifungal activity towards Candida albicans and non-albicans Candida species strains. The aromatic biphenyl ester derivatives 6a-c were more active than the reference compound fluconazole. 6c possesses a MIC mean values of 1.7 ± 1.4 μg mL(-1)vs C. albicans and 1.9 ± 2.0 μg mL(-1)vs non-albicans Candida species strains. The racemic mixtures of 6a, b were purified to afford the pure enantiomers. The (-) isomers were up to 500 times more active than (+) isomers. (-)-6a and (-)-6b were thirty and ninety times more active than fluconazole towards C. krusei strain respectively. The racemates of 6a-c showed low cytotoxicity against human monocytic cell line (U937) with 6a demonstrating a CC(50) greater than 128 μg mL(-1).

Activity of caffeic acid derivatives against Candida albicans biofilm

The aim of this study was to evaluate the caffeic acid (1) and ester derivatives (2-10) against Candida albicans biofilm and to investigate whether these compounds are able to inhibit the biofilm formation or destroy pre-formed biofilm. Caffeic acid ester 7, cinnamic acid ester 8 and 3,4-dihydroxybenzoic acid ester 10 are more active than fluconazole, used as reference drug, both on biofilm in formation with MIC50 values of 32, 32 and 16μg/mL, respectively, and in the early stage of biofilm formation (4h) with MIC50 values of 64, 32 and 64μg/mL, respectively. These esters result also more active than fluconazole on mature biofilm (24h), especially 8 and 10 with MIC50 values of 64μg/mL.

Structural Basis for Rational Design of Inhibitors Targeting Trypanosoma cruzi Sterol 14α-Demethylase: Two Regions of the Enzyme Molecule Potentiate Its Inhibition

Chagas disease, which was once thought to be confined to endemic regions of Latin America, has now gone global, becoming a new worldwide challenge with no cure available. The disease is caused by the protozoan parasite Trypanosoma cruzi, which depends on the production of endogenous sterols, and therefore can be blocked by sterol 14α-demethylase (CYP51) inhibitors. Here we explore the spectral binding parameters, inhibitory effects on T. cruzi CYP51 activity, and antiparasitic potencies of a new set of β-phenyl imidazoles. Comparative structural characterization of the T. cruzi CYP51 complexes with the three most potent inhibitors reveals two opposite binding modes of the compounds ((R)-6, EC50 = 1.2 nM, vs (S)-2/(S)-3, EC50 = 1.0/5.5 nM) and suggests the entrance into the CYP51 substrate access channel and the heme propionate-supporting ceiling of the binding cavity as two distinct areas of the protein that enhance molecular recognition and therefore could be used for the development of more effective antiparasitic drugs.

Inhibition of the α-carbonic anhydrase from Vibrio cholerae with amides and sulfonamides incorporating imidazole moieties

Abstract We discovered novel and selective sulfonamides/amides acting as inhibitors of the α-carbonic anhydrase (CA, EC 4.2.1.1) from the pathogenic bacterium Vibrio cholerae (VchCA). This Gram-negative bacterium is the causative agent of cholera and colonises the upper small intestine where sodium bicarbonate is present at a high concentration. The secondary sulfonamides and amides investigated here were potent, low nanomolar VchCA inhibitors whereas their inhibition of the human cytosolic isoforms CA I and II was in the micromolar range or higher. The molecules represent an interesting lead for antibacterial agents with a possibly new mechanism of action, although their CA inhibition mechanism is unknown for the moment.

New promising compounds with in vitro nanomolar activity against Trypanosoma cruzi

The antiparasitic activity of azole and new 4-aminopyridine derivatives has been investigated. The imidazoles 1 and 3-5 showed a potent in vitro antichagasic activity with IC50 values in the low nanomolar concentration range. The (S)-1, (S)-3, and (S)-5 enantiomers showed (up to) a thousand-fold higher activity than the reference drug benznidazole and furthermore low cytotoxicity on rat myogenic L6 cells.

(Thiazol-2-yl)hydrazone derivatives from acetylpyridines as dual inhibitors of MAO and AChE: synthesis, biological evaluation and molecular modeling studies

Abstract Several (thiazol-2-yl)hydrazone derivatives from 2-, 3- and 4-acetylpyridine were synthesized and tested against human monoamine oxidase (hMAO) A and B enzymes. Most of them had an inhibitory effect in the low micromolar/high nanomolar range, being derivatives of 4-acetylpyridine selective hMAO-B inhibitors also at low nanomolar concentrations. The structure–activity relationship, as confirmed by molecular modeling studies, proved that the pyridine ring linked to the hydrazonic nitrogen and the substituted aryl moiety at C4 of the thiazole conferred the inhibitory effects on hMAO enzymes. Successively, the strongest hMAO-B inhibitors were tested toward acetylcholinesterase (AChE) and the most interesting compound showed activity in the low micromolar range. Our results suggest that this scaffold could be further investigated for its potential multi-targeted role in the discovery of new drugs against the neurodegenerative diseases.

Pharmacophore Assessment Through 3-D QSAR: Evaluation of the Predictive Ability on New Derivatives by the Application on a Series of Antitubercular Agents

Pharmacophoric mapping is a useful procedure to frame, especially when crystallographic receptor structures are unavailable as in ligand-based studies, the hypothetical site of interaction. In this study, 71 pyrrole derivatives active against M. tuberculosis were used to derive through a recent new 3-D QSAR protocol, 3-D QSAutogrid/R, several predictive 3-D QSAR models on compounds aligned by a previously reported pharmacophoric application. A final multiprobe (MP) 3-D QSAR model was then obtained configuring itself as a tool to derive pharmacophoric quantitative models. To stress the applicability of the described models, an external test set of unrelated and newly synthesized series of R-4-amino-3-isoxazolidinone derivatives found to be active at micromolar level against M. tuberculosis was used, and the predicted bioactivities were in good agreement with the experimental values. The 3-D QSAutogrid/R procedure proved to be able to correlate by a single multi-informative scenario the different activity molecular profiles thus confirming its usefulness in the rational drug design approach.

Exploring the anti-biofilm activity of cinnamic acid derivatives in Candida albicans

Some compounds, characterized by phenylethenyl moiety, such as methyl cinnamate and caffeic acid phenethyl ester, are able to inhibit C. albicans biofilm formation. On these bases, and as a consequence of our previous work, we synthesized a series of cinnamoyl ester and amide derivatives in order to evaluate them for the activity against C. albicans biofilm and planktonically grown cells. The most active compounds 7 and 8 showed ⩾50% biofilm inhibition concentrations (BMIC50) of 2μg/mL and 4μg/mL respectively, against C. albicans biofilm formation; otherwise, 7 showed an interesting activity also against mature biofilm, with BMIC50 of 8μg/mL.

Carprofen Analogues as Sirtuin Inhibitors: Enzyme and Cellular Studies

The best of both: SIRT1/2 inhibitors were developed by combining chemical features of selisistat (SIRT1-selective inhibitor; blue) and carprofen (anti-inflammatory drug; red). The most potent compound (shown) increased acetyl-p53 and acetyl-α-tubulin levels, and induced slight apoptosis at 50 μM in U937 cells, differently from selisistat and carprofen.

In vitro screening of 2-(1H-imidazol-1-yl)-1-phenylethanol derivatives as antiprotozoal agents and docking studies on Trypanosoma cruzi CYP51

Sterol 14α-demethylase (CYP51) is a key enzyme involved in the survival and virulence of many parasite protozoa, such as Trypanosoma and Leishmania species, thus representing a valuable drug target for the treatment of Kinetoplastid diseases. A set of azole-based compounds selected from an in-house compound library was in vitro screened against different human protozoan parasites. Several compounds showed selective activity against Trypanosoma cruzi, with compound 7 being the most active (IC50 = 40 nM). Given the structural similarity between the compounds here reported and known CYP51 inhibitors, a molecular docking study was performed to assess their binding with protozoal target and to rationalize the biological activity data.