Me Marongiu

3,4-Dihydro-2-Alkoxy-6-Benzyl-4-Oxopyrimidines (DABOs): A New Class of Specific Inhibitors of Human Immunodeficiency Virus Type 1

A series of novel 3,4-dihydro-6-benzyl-4-oxopyrimidines substituted at both the C-5 and the C-2 positions were synthesized as potential anti-HIV agents. Preparation of the title compounds was achieved by condensation of O-methylisourea with methyl 2-alkyl-4-phenylacetylacetate and subsequent displacement of the methoxy group by reaction with a series of linear, ramified and cyclic alkoxy groups containing from three to six carbon units. Methyl 2-alkyl-4-phenylacetylacetates were prepared by alkylation of methyl 4-phenylacetylacetate, which was obtained starting from Meldrums acid and phenacetyl chloride. Acid hydrolysis of 3,4-dihydro-6-benzyl-2-methoxy-4-oxopyrimidines furnished the corresponding 1,2,3,4-tetrahydro-6-benzyl-2,4-dioxopyrimidines. In acutely infected MT-4 cells, compounds 3e, 3o, 3q and 3r showed an anti-HIV-1 activity as potent and/or selective as HEPT and ddl. Unlike HEPT, the replacement of a methyl for an hydrogen atom at position C-5 of 3,4-dihydro-2-alkoxy-6-benzyl-4-oxopyrimidines (DABOs) did not abolish the antiviral activity, as well as the substitution of the C-5 methyl for an ethyl group did not increase the potency. However, similarly to HEPT and its derivatives, DABOs targeted the HIV-1 reverse transcriptase and neither inhibited the multiplication of HIV-2 in acutely infected MT-4 cells, nor that of HIV-1 in chronically infected H9/IIIB cells.

Synthesis, antimicrobial and antiviral activities of isotrimethoprim and some related derivatives

Abstract The synthesis and the antimicrobial activities of 2,4-diamino-6-(3,4,5-trimethoxybenzyl)pyrimidine (isotrimethoprim) and some related derivatives are reported. The new derivatives have been found scarcely active against bacteria and fungi, with the only exception of 4-chloro-2-methoxypyrimidinyl-3,4,5-trimethoxyphenyldichloromethane, which showed good antibacterial activity against Staphylococcus aureus . Cytotoxicity and antiviral assays, HIV included, have also been determined in comparison with TMP and AZT. Little but selective activity was shown by some derivatives against HIV retrovirus.

Synthesis and Biological Evaluation of 5H-Indolo [3,2-b][1,5]Benzothiazepine Derivatives, Designed as Conformationally Constrained Analogues of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Inhibitor L-737,126

In the presence of sodium hydride, reaction of aryldisulphides with ethyl esters of indole-2-carboxylic acids furnished ethyl 3-arylthioindole-2-carboxy-lates, which were cyclized intramolecularly to afford 5H-indolo[3,2-b][1,5]benzothiazepin-6(7H)-ones or hydrolysed in alkaline medium to give 3-arylthioindole-2-carboxylic acids. These acids, also obtained by the action of aryldisulphides on indole-2-carboxylic acids, afforded tetracyclic 5H-indolo [3,2-b][1,5]benzothiazepin-6(7H)-ones upon treatment with EDCI–DMAP. Transformation of cyclic sulphides into the required sulphones was achieved by treatment with hydrogen peroxide or with m-chloroperbenzoic acid. The title derivatives are conformationally constrained analogues of the potent human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor 3-benzene-sulphonyl-5-chloroindole-2-carboxamide (L-737, 126). Although the indolobenzothiazepine derivatives, as well as the indolyl aryl sulphones used for their synthesis, were endowed with anti-HIV-1 activities in the submicromolar and micromolar range, none of them proved more potent than L-737,126.

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.

Targeting HIV: old and new players.

Despite the unprecedented successes in the therapy of HIV infection, AIDS remains a major world health problem being the first cause of death in Africa and the fourth leading cause of death worldwide. Rapid emergence of drug-resistant HIV variants and severe side effects limit the efficacy of existing therapies. The intrinsic high variability of HIV calls for combining different drugs with distinct mode of action to achieve synergistic antiviral activity. Efforts are being made to develop agents addressing new steps in HIV replication and to optimize both antiviral activity and pharmacokinetic of the current drugs targeting reverse transcriptase and protease. The class of viral entry inhibitors is undergoing evaluation for both systemic and topical administration, and compounds targeting the fusion step may be the first to reach the market. Identification of compounds unambiguously affecting HIV replication by targeting integrase supports the potential of this crucial viral enzyme as a drug target. Targeting HIV gene regulation, which could also lead to cellular toxicity, may also become an important discovery strategy, provided that inhibitors with sufficient specificity are identified. In this review we will summarize the current understanding of the key steps in HIV life cycle in the context of representative inhibitors based on their modes of action. We then present a summary of compounds under clinical development, with the aim of providing a picture of the current potential for targeting HIV.

Synthesis and evaluation of cytostatic and antiviral activities of 3' and 4'-avarone derivatives

A series of 3′ and 4′-substituted avarone derivatives were synthesized and tested in culture systems as antitumour and antiviral agents in comparison to avarol and avarone. 3′-alkylamino derivatives showed potent cytostatic activities against murine L1210 and human B (Raji) and T (C8166, H9) lymphoblast cells (ID50 range 1.7–3.7 μm). Avarol and avarone were six times less active. While none of the derivatives showed anti-human immunodeficiency virus (HIV) activity superior to that of the parent compounds, most of them, avarol and avarone included, were potent and selective inhibitors of poliovirus multiplication.

Different molecular mechanisms of inhibition of bovine viral diarrhea virus and hepatitis C virus RNA-dependent RNA polymerases by a novel benzimidazole.

The virus-encoded RNA-dependent RNA polymerase (RdRp) has emerged as a primary target in the search for selective inhibitors of Flaviviridae. Recently, we reported on the selective inhibition, in cell-based assays, of both BVDV (EC50 = 0.80 ± 0.06 μM) and HCV (EC50 = 1.11 ± 0.15 μM) by 2-{1-[2-(2,4-dimethoxyphenyl)-1H-benzimidazol-5-yl]ethylidene}hydrazinecarbothioamide (227G). Here we show that, in enzyme assays with recombinant enzymes, 227G inhibits, in a dose-dependent manner, the RdRp of both BVDV (IC50 = 0.0020 ± 0.0004 μM) and HCV (IC50 = 0.40 ± 0.04 μM). Furthermore, we report on the selection and molecular analysis of a BVDV-resistant mutant, characterized by the presence of the I261M mutation. By applying a multilevel computational approach, we identified different 227G binding sites on the two RdRps. They were further validated by the good agreement between the calculated affinities and those extrapolated from IC50 values. Our findings suggest different molecular mechanisms of inhibition of the HCV and BVDV RdRps by 227G and indicate the importance of understanding ligand-enzyme interactions at the molecular level for the rational design of new and more potent leads.

8-Aza Derivatives of 3-Deazapurine Nucleosides. Synthesis and in vitro Evaluation of Antiviral and Antitumor Activity

The syntheses of 4-amino-1-(β-D-ribofuranosyl)-1H-1,2,3-triazolo[4,5-c]pyridine (8-aza-3-deazaadenosine, 1), 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-1H-1,2,3-triazolo[4,5-c]pyridine (2′-deoxy-8-aza-3-deazaadenosine, 2), and their N8 and N7 glycosylated analogues (12,13, 21,22) and 4-amino-1-(2,3-dideoxy-β-D-erythro-pentof uranosyl)-1H-1,2,3-triazolo [4,5-c]pyridine (2′,3′-dideoxy-8-aza-3-deazaadenosine, 3) were carried out by glycosylation of the 4-chloro-3H-1,2,3-triazolo[4,5-c]pyridine anion. The anomeric configuration as well as the position of glycosylation were determined by 1H-, 13C-NMR, UV and N.O.E. difference spectroscopy. Nucleoside (2) and its parent compound 2′-deoxy-3-deazaadenosine were found active against ASFV and VSV. The 4-chloro-2-(β-D-ribofuranosyl)-2H-1,2,3-triazolo[4,5-c] pyridine (9) was active against Coxsackie B1, whereas none of the 8-aza-3-deaza purine nucleosides, compound (3) included, was active against HIV-1. The 6-chloro derivatives of 8-aza-3-deazapurine ribo- and 2′-deoxyribonucleosides (11) and (20) showed some activity against LoVo human colon adenocarcinoma.

On the inhibitory effect of 2-amino-4,6-dichloropyrimidine on growth of vaccinia virus.

2-Amino-4,6-dichloropyrimidine prevents mutation of Vaccinia virus. Proteins synthesized in the presence of the drug are not assembled into virions.

Potent and Selective Inhibitors of Human Immunodeficiency Virus Protease Structurally Related to L-694,746:

A series of human immunodeficiency virus (HIV) protease inhibitors, which are analogues of N-[2(R)-hydroxy-1(S)-indanyl]-5(S)-[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-(R)-[[4-(carboxymethoxy)phenyl]methyl]hexanamide (L-694,746), a metabolite of the anti-HIV agent L-689,502, were synthesized. In these compounds, the acetic group linked to the para position of the P1′ phenyl in the reference inhibitor was replaced either by the bioisosteric phosphonomethoxy group and its diisopropyl/dibenzyl derivatives, or the 1H-tetrazol-5-yl-methoxy group and its 1-benzyl derivative. In enzyme assays, phosphonomethoxy and tetrazolmethoxy analogues proved to be potent inhibitors of the HIV-1 protease, with IC50 values as low as 0.04 nM. When tested for anti-HIV-1 activity in cell-based assays, most of the new derivatives proved active, with benzyl derivatives being more active than their highly polar, unsubstituted counterparts. The dibenzylphosphonomethoxy analogue was the most active compound, with an EC50 value of 10 nM and a selectivity index of 20 000. When compounds were examined for their capability to reduce p24 levels in both acutely and chronically infected MT-4 and H9/IIIB cells, all of them were found to be active at concentrations close to those capable of preventing HIV-1-induced cytopathic effect.