Luigi Scipione

Structure–Activity Relationship of Pyrrolyl Diketo Acid Derivatives as Dual Inhibitors of HIV-1 Integrase and Reverse Transcriptase Ribonuclease H Domain

The development of HIV-1 dual inhibitors is a highly innovative approach aimed at reducing drug toxic side effects as well as therapeutic costs. HIV-1 integrase (IN) and reverse transcriptase-associated ribonuclease H (RNase H) are both selective targets for HIV-1 chemotherapy, and the identification of dual IN/RNase H inhibitors is an attractive strategy for new drug development. We newly synthesized pyrrolyl derivatives that exhibited good potency against IN and a moderate inhibition of the RNase H function of RT, confirming the possibility of developing dual HIV-1 IN/RNase H inhibitors and obtaining new information for the further development of more effective dual HIV-1 inhibitors.

6-(1-Benzyl-1H-pyrrol-2-yl)-2,4-dioxo-5-hexenoic acids as dual inhibitors of recombinant HIV-1 integrase and ribonuclease H, synthesized by a parallel synthesis approach.

The increasing efficiency of HAART has helped to transform HIV/AIDS into a chronic disease. Still, resistance and drug-drug interactions warrant the development of new anti-HIV agents. We previously discovered hit 6, active against HIV-1 replication and targeting RNase H in vitro. Because of its diketo-acid moiety, we speculated that this chemotype could serve to develop dual inhibitors of both RNase H and integrase. Here, we describe a new series of 1-benzyl-pyrrolyl diketohexenoic derivatives, 7a-y and 8a-y, synthesized following a parallel solution-phase approach. Those 50 analogues have been tested on recombinant enzymes (RNase H and integrase) and in cell-based assays. Approximately half (22) exibited inhibition of HIV replication. Compounds 7b, 7u, and 8g were the most active against the RNase H activity of reverse-transcriptase, with IC50 values of 3, 3, and 2.5 μM, respectively. Compound 8g was also the most potent integrase inhibitor with an IC50 value of 26 nM.

Basic quinolinonyl diketo acid derivatives as inhibitors of HIV integrase and their activity against RNase H function of reverse transcriptase

A series of antiviral basic quinolinonyl diketo acid derivatives were developed as inhibitors of HIV-1 IN. Compounds 12d,f,i inhibited HIV-1 IN with IC50 values below 100 nM for strand transfer and showed a 2 order of magnitude selectivity over 3′-processing. These strand transfer selective inhibitors also inhibited HIV-1 RNase H with low micromolar potencies. Molecular modeling studies based on both the HIV-1 IN and RNase H catalytic core domains provided new structural insights for the future development of these compounds as dual HIV-1 IN and RNase H inhibitors.

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).

Choline pivaloyl esters improve in rats cognitive and memory performances impaired by scopolamine treatment or lesions of the nucleus basalis of Meynert.

The effects of two choline pivaloyl esters, [2-(2,2-dimethylpropionyloxy)ethyl]trimethylammonium iodide (1) and [2-(2,2-dimethylpropionyloxy)ethyl]trimethylammonium 2,2-dimethylpropionate (2), on learning and memory impairments induced in rats by scopolamine or lesions of nucleus basalis magnocellularis (NBM) have been evaluated by object recognition and Morris water maze tests in comparison with Tacrine (THA). Both 1 and 2 restored discrimination in object recognition test for assessing working-episodic memory and improved spatial memory in scopolamine or NBM-lesioned rats as well. The positive effects produced by 1 and 2 on cognitive and memory deficits were well comparable with those evoked by THA, used as reference compound.

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.

New systems for the specific delivery and sustained release of dopamine to the brain

Abstract The present paper reports the synthesis of the chemical delivery system 5 and dopamine (DA) prodrug 6 as well as their application for the specific delivery and sustained release of DA to the rat brain. The ability of 5 and 6 to penetrate the blood-brain barrier (BBB) and release DA into the central nervous system (CNS) was assessed by comparing, on a molar basis, the behavioural effects produced by DA itself and the above compounds, when centrally or peripherally administered in conscious rats. When intravenously injected, both derivatives 5 and 6 elicited vacuous chewing behaviours comparable with those induced by intracerebroventricular (icv) injection of the parent drug. These results suggest that 5 and 6 are able to cross the BBB and enter the CNS, releasing DA. Furthermore, a long lasting effect was observed for the tripivaloyl-derivative 6, likely due to a slower release of DA following from an increased resistance of the sterically hindered pivaloylamide group to enzymatic hydrolysis. It must be pointed out that the α-adrenergic effect (piloerection) observed after DA was peripherally injected was not observed after systemic administration of the compounds 5 and 6. This finding may indicate that neither the chemical delivery system 5 nor the prodrug 6 release free DA at bioactive concentrations at a peripheral level.

On the structure of intermediate adducts arising from dithionite reduction of pyridinium salts: a novel class of derivatives of the parent sulfinic acid

Abstract 13C and 17O NMR spectroscopy show that adducts arising from dithionite reduction of 3- or 3,5-cyano- or carbamoyl-substituted pyridinium salts to the corresponding 1,4-dihydropyridines, are S-anions of esters of the simplest parent sulfinic acid. A pathway for formation of the 1,4-dihydropyridines, involving an intramolecular hydride transfer, is suggested.

Design, synthesis, and structure-activity relationship of N-arylnaphthylamine derivatives as amyloid aggregation inhibitors.

Dyes like CR are able to inhibit the aggregation of Aβ fibrils. Thus, a screening of a series of dyes including ABBB (1) was performed. Its main component 2 tested in an in vitro assay (i.e., ThT assay) showed good potency at inhibiting fibrils association. Congeners 4-9 have been designed and synthesized as inhibitors of Aβ aggregation. A number of these newly synthesized compounds have been found to be active in the ThT assay with IC(50) of 1-57.4 μM. The most potent compound of this series, 4k, showed micromolar activity in this test. Another potent derivative 4q (IC(50) = 5.6 μM) rapidly crossed the blood-brain barrier, achieving whole brain concentrations higher than in plasma. So 4q could be developed to find novel potent antiaggregating βA agents useful in Alzheimer disease as well as other neurological diseases characterized by deposits of amyloid aggregates.

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.