Anna Giulia Loi

Synthesis and Antiviral Activity of New 3,4-Dihydro-2-Alkoxy-6-Benzyl-4-Oxopyrimidines (DABOs), Specific Inhibitors of Human Immunodeficiency Virus Type 1

3,4-Dihydro-2-alkoxy-6-benzyl-4-oxopyrimidines (DABOs) have emerged as non-nucleoside inhibitors of human immunodeficiency virus type 1 [Artico et al. (1993), Antiviral Chem Chemother 4: 361-368]. With a view to increasing their potency, a new series of DABO derivatives, differently substituted at positions C-2 and/or C-5 of the pyrimidine ring and 3′ or 3′,5′ of the benzyl moiety, have been synthesized. DABOs were prepared by reacting O-methylisourea with the appropriate methyl 2-alkyl-4-phenylacetylacetate, with formation of 3,4-dihydro-2-methoxy-6-arylmethyl-4-oxopyrimidines. Subsequent displacement of the methoxy group linked at the 2-position of the pyrimidine ring by treatment with alkoxy and cycloalkoxy potassium salts led to the required derivatives. In vitro, the most potent compounds were 12e and 12p, which had an EC50 of 0.8 μM and a selective index of 400.

2'-C-Methyl branched pyrimidine ribonucleoside analogues : potent inhibitors of RNA virus replication

RNA viruses are the agents of numerous widespread and often severe diseases. Their unique RNA-dependent RNA polymerase (RDRP) is essential for replication and, thus, constitutes a valid target for the development of selective chemotherapeutic agents. In this regard, we have investigated sugar-modified ribonucleoside analogues as potential inhibitors of the RDRP. Title compounds retain ‘natural’ pyrimidine bases, but possess a β-methyl substituent at the 2′-position of the D- or L-ribose moiety. Evaluation against a broad range of RNA viruses, either single-stranded positive (ssRNA), single-stranded negative (ssRNA−) or double-stranded (dsRNA), revealed potent activities for D-2′-C-methyl-cytidine and -uridine against ssRNA+, and dsRNA viruses. None of the L-enantiomers were active. Moreover, the 5′-triphosphates of the active D-enantiomers were found to inhibit the bovine virus diarrhoea virus polymerase. Thus, the 2′-methyl branching of natural pyrimidine ribonucleosides transforms physiological molecules into potent, broad-spectrum antiviral agents that merit further development.

5H-pyrrolo[1,2-b] [1,2,5]benzothiadiazepines (PBTDs): a novel class of non-nucleoside reverse transcriptase inhibitors.

With the aim of developing novel inhibitors of human immunodeficiency virus, various derivatives (10-17) related to 5H-pyrrolo[1,2-b] [1,2,5]benzothiadiazepine (PBTD) were prepared and tested in vitro. The title tricyclic derivatives were obtained by intramolecular cyclization of the open-chain intermediate arylpyrrylsulfones, followed by N-alkylation at position 10. Among test derivatives some 10-alkyl-5H-pyrrolo[1,2-b] [1,2,5]benzothiadiazepin-11(10H)-one-5,5-dioxides were found to exert potent and specific activity against HIV-1. In particular, 7-chloro derivatives 11i and j showed a potency comparable to that of nevirapine. However, when the chloro atom was shifted to the 8 position, the related products were scarcely active or totally inactive. Replacement of the pyrrole with pyrrolidine led to inactive products and the reduction of SO2 to S strongly diminished the antiviral potency. PBTD derivatives active in cell cultures were also inhibitory to the recombinant HIV-1 RT in enzyme assays, thus allowing the conclusion that PBTDs are a new class of non-nucleoside reverse transcriptase inhibitors (NNRTIs).

Glycosidopyrroles. Part 1. Acyclic derivatives: 1-(2-hydroxyethoxy)methylpyrroles as potential anti-viral agents.

Acyclic glycosidopyrroles of type 1, synthesized in good overall yields, were evaluated for anti-viral activity. Compound 10i was found to inhibit the HIV-1 replication at concentrations that were very close to those cytotoxic for MT-4 cells. Compounds 10a,f,i inhibited both strains HSV-1 and HSV-2 at concentrations slightly below those cytotoxic for Vero cells. However for this series of glycosidopyrroles some relationship between calculated log P values and the observed cytotoxicity was found.

1,2,5-Benzothiadiazepine and Pyrrolo[2,1-d]-[1,2,5]Benzothiadiazepine Derivatives with Specific Anti-Human Immunodeficiency Virus Type 1 Activity

We synthesized and tested as novel inhibitors of human immunodeficiency virus type 1 (HIV-1) bi- and tricyclic thiadiazine ring homologues of 7-chloro-2-ethyl-2H-1,2,4-benzothiadiazin-3-(4H)-one 1,1-dioxide, which is a compound endowed with anti-HIV-1 activity at low micromolar concentrations. Benzothiadiazepine derivatives were obtained by alkylation of 8-chloro-2,3-dihydro-3-methyl-1,2,5-benzothiadiazepin-4(5H)-one 1,1-dioxide, which was obtained by intramolecular cyclization of 2-(2-amino-5-chloro-benzenesulphonamido) propanoic acid. Pyrrolobenzothiadiazepines were synthesized from N-substituted 5-chloro-2-(1H-pyrrol-1-yl)benzenesulphonamides by treating with triphosgene. N6-substituted pyrrolo[2,1-d][1,2,5]benzothiadiazepin-7(6H)-one 5,5-dioxides were active, thoughnot very potent. Both a chlorine atom and an unsaturated alkyl chain were found to be determinants of anti-HIV-1 activity. The highest potency was shown by a derivative with a TIBO-related 3,3-dimethylallyl chain. 2,3-Dihydro-1,2,5-benzothiadiazepin-4(5H)-one 1,1-dioxides were scarcely active in HIV-1-infected MT-4 cell assays; however, the introduction of the dimethylallyl chain into 7-chloro-1,2,5-benzothiadiazepine moiety led to a bicyclic derivative which was more potent and less cytotoxic than the tricyclic pyrrole-containing counterpart.

A NEW CLASS OF ACYCLIC NUCLEOSIDE PHOSPHONATES: SYNTHESIS AND BIOLOGICAL ACTIVITY OF 9-{[(PHOSPHONOMETHYL)AZIRIDIN-1-YL]METHYL}GUANINE (PMAMG) AND ANALOGUES

ABSTRACT A new class of acyclic nucleoside phosphonates PMAMG, PMAMA, PMAMC, and PMAMT (compounds 1, 2, 3 and4) have been synthesized and tested in vitro against a wide variety of viruses, fungi and bacteria. PMAMG (1) was synthesized by the alkylation reaction of acetylguanine with the phosphonate side-chain, diisopropyl {[2-(bromomethyl)aziridin-1-yl]methyl}phosphonate (9), followed by deesterification reaction in the presence of TMSBr. In similar way, PMAMA, PMAMC, and PMAMT were prepared.

Computer-assisted design, synthesis and biological evaluation of novel pyrrolyl heteroaryl sulfones targeted at HIV-1 reverse transcriptase as non-nucleoside inhibitors

Three pyrrolyl heteroaryl sulfones (ethyl 1-[(1H-benzimidazol-2(3H)one-5-yl)sulfonyl]-1H-pyrrole-2-carboxyla te, ethyl 1-[(1H-benzimidazol-5(6)-yl)sulfonyl]-1H-pyrrole-2-carboxylate and ethyl 1-[(1H-benzotriazol-5(6)-yl)sulfonyl]-1H-pyrrole-2-carboxylate) were designed as novel HIV-1 reverse transcriptase non-nucleoside inhibitors using structure-based computational methods. Although these compounds were inactive in the cell-based assay, they inhibited the target enzyme with micromolar potency (IC50s = 2 microM, 3 microM and 9 microM, respectively).

Acyclic Nucleotides Related to Clitocine: Synthesis and Anti-HIV Activity

Abstract The syntheses and antiviral activity of analogues of the anti-HIV agents PMEA, PMEDAP, (R)-PMPA, (R)-PMPDAP are described. In these analogues the adenine moiety is replaced by 4,6-diamino-5-nitro-pyrimidine (the aglycon of clitocine) or 2,4,6-triamino-5-nitro-pyrimidine. The synthesis of similar acyclic phosphonates related to PMEG and (R)-2′-methyl-PMEG is also reported. Some compounds proved to be active as anti-HIV agents.

1-Arylsulfonyl-3-(α-hydroxybenzyl)-1H-pyrroles, a novel class of anti-HIV-1 reverse transcriptase inhibitors

Abstract Various 1-arylsulfonyl-3-(α-hydroxybenzyl)-1H-pyrroles were prepared by Friedel-Crafts reaction of 1-arylsulfonyl-1H-pyrroles with aroylchlorides in the presence of aluminum trichloride, followed by reduction of the ketones to the required carbinols. Title compounds were identified as a novel class of non-nucleoside HIV-1 reverse transcriptase inhibitors characterized by the presence of a diarylcarbinol moiety, a chemical feature that strictly correlates with the anti-HIV-1 activity.

Synthesis of potent and broad genotypically active NS5B HCV non-nucleoside inhibitors binding to the thumb domain allosteric site 2 of the viral polymerase.

The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells and, as a consequence, is an attractive target for selective inhibition. This Letter describes the discovery of a new family of HCV NS5B non-nucleoside inhibitors, based on the bioisosterism between amide and phosphonamidate functions. As part of this program, SAR in this new series led to the identification of IDX17119, a potent non-nucleoside inhibitor, active on the genotypes 1b, 2a, 3a and 4a. The structure and binding domain of IDX17119 were confirmed by X-ray co-crystallization study.