Silvano Tortorella

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).

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.

Covalent adducts from 1,3-disubstituted pyridinium salts and piperidine

Abstract Covalent adducts 3a-f have been isolated from the reaction between piperidine and pyridinium salts 1a-f. 3a-f are stable both in the solid state and in apolar solvents, whereas their fast dissociation back to piperidine and pyridinium ions occurs in aqueous solution. The latter, in the alkaline environment produced by the amine, yields the correspondent pseudobases, which are key intermediates of the subsequent reactions. For instance, the pseudobases from 1a,b can undergo either a ring-opening reaction or a redox process with the corresponding pyridinium cations.

On the regio- and stereoselectivity of pyridinyl radical dimerization

The present work was carried out in order to elucidate the combined effects of the electron spin density on the ring carbons and the steric hindrance of the ring substituents upon the regio- and stereoselectivity of the dimerization of 3-carbamoyl- and 3-cyanopyridinyl radicals. To this purpose the composition of mixtures of diastereoisomeric dimers arising from the one-electron electrochemical reduction of several 3-carbamoyl and 3-cyano substituted pyridinium salts has been studied by 1H NMR spectroscopy. In some cases, single diastereoisomers have been isolated from mixtures by preparative HPLC.The results show that: (a) hindering steric effect of substituents at coupling sites prevails over electron spin density on coupling carbons in governing regioselectivity of 3-carbamoylpyridinyl radical dimerization; (b) large bulky N-ring substituents produce a significant shielding effect on the adjacent dimerization site; (c) the relative amounts of diastereoisomers in the mixtures of 4,4′- and 6,6′-linked dimers indicate that the dimerization process is largely stereoselective; (d) otherwise, nearly equal amounts of 4,4′- and 4,6′-linked dimers, and relative diastereoisomers as well, arise from the reduction of 3-cyano substituted pyridinium salts. This finding indicates that the presence of the carbamoyl substituent at the 3 position is a primary factor in inducing the regio- and stereoselectivity of pyridinyl radical dimerization.

Reactivity of pseudobases from pyridinium salts competition between hydrogen transfer and ring-opening reactions

Abstract The reactions of 3-cyano-1-methylpyridinium iodide (1a) and l-benzyl-3-cyanopyridinium chloride (1b) in aqueous NaOH have been studied over a range of concentrations from N 0.5 to N 2.5 with respect to the hydroxide ion, and with the concentrations of the reactants at different ratios. It has been found that the intermediate, not isolable pseudobases can undergo, depending on the experimental conditions, two competitive reaction channels, namely, a redox process leading to the dihydropyridines 3–5 and pyridones 2,6, and a ring-opening reaction leading to the pentadienenitrile 7, 2-imino-3-pyridinecarbaldehyde 8, and 2-(aryl)alkylamino-3-pyridinecarbaldehyde 9.

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.