Discovery and Optimization of a Compound Series Active against , the Causative Agent of Chagas Disease.

Chagas disease is caused by the protozoan parasite . It is endemic in South and Central America and recently has been found in other parts of the world, due to migration of chronically infected patients. The current treatment for Chagas disease is not satisfactory, and there is a need for new treatments.

Validation of Plasmodium falciparum dUTPase as the target of 5'-tritylated deoxyuridine analogues with anti-malarial activity.

Background: Malaria remains as a major global problem, being one of the infectious diseases that engender highest mortality across the world. Due to the appearance of resistance and the lack of an effective vaccine, the search of novel anti-malarials is required. Deoxyuridine 5'-triphosphate nucleotido-hydrolase (dUTPase) is responsible for the hydrolysis of dUTP to dUMP within the parasite and has been proposed as an essential step in pyrimidine metabolism by providing dUMP for thymidylate biosynthesis.

Investigation of acyclic uridine amide and 5'-amido nucleoside analogues as potential inhibitors of the Plasmodium falciparum dUTPase.

Previously we have shown that trityl and diphenyl deoxyuridine derivatives and their acyclic analogues can inhibit Plasmodium falciparum dUTPase (PfdUTPase). We report the synthesis of conformationally restrained amide derivatives as inhibitors PfdUTPase, including both acyclic and cyclic examples. Activity was dependent on the orientation and location of the amide constraining group.

Discovery of 4'-azido-2'-deoxy-2'-C-methyl cytidine and prodrugs thereof: a potent inhibitor of Hepatitis C virus replication.

4'-Azido-2'-deoxy-2'-methylcytidine (14) is a potent nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase, displaying an EC(50) value of 1.2 μM and showing moderate in vivo bioavailability in rat (F=14%). Here we describe the synthesis and biological evaluation of 4'-azido-2'-deoxy-2'-methylcytidine and prodrug derivatives thereof.

Design, synthesis, and evaluation of 5'-diphenyl nucleoside analogues as inhibitors of the Plasmodium falciparum dUTPase.

Deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase) is a potential drug target for malaria. We previously reported some 5'-tritylated deoxyuridine analogues (both cyclic and acyclic) as selective inhibitors of the Plasmodium falciparum dUTPase. Modelling studies indicated that it might be possible to replace the trityl group with a diphenyl moiety, as two of the phenyl groups are buried, whereas the third is exposed to solvent.

β-Branched acyclic nucleoside analogues as inhibitors of Plasmodium falciparum dUTPase.

We report a series of β-branched acyclic tritylated deoxyuridine analogues as inhibitors of Plasmodium falciparum deoxyuridine-5'-triphosphate nucleotidohydrolase (PfdUTPase), an enzyme involved in nucleotide metabolism that acts as first line of defence against uracil incorporation into DNA. Compounds were assayed against both PfdUTPase and intact parasites showing a correlation between enzyme inhibition and cellular assays. β-Branched acyclic uridine analogues described here showed equal or slightly better potency and selectivity compared with previously reported analogues.

Modified 5'-trityl nucleosides as inhibitors of Plasmodium falciparum dUTPase.

2'-Deoxyuridine triphosphate nucleotidohydrolase (dUTPase) is a potential drug target for the treatment of malaria. We previously reported the discovery of 5'-tritylated analogues of deoxyuridine as selective inhibitors of this Plasmodium falciparum enzyme. Herein we report further structure-activity studies; in particular, variations of the 5'-trityl group, the introduction of various substituents at the 3'-position of deoxyuridine, and modifications of the base.

Profound antiviral effect of oral administration of MIV-210 on chronic hepadnaviral infection in a woodchuck model of hepatitis B.

MIV-210 is a prodrug of 3'-fluoro-2',3'-dideoxyguanosine with high oral bioavailability in humans and potent activity against hepatitis B virus (HBV). Woodchucks infected with woodchuck hepatitis virus (WHV) represent an accurate model of HBV infection that is utilized for evaluation of the efficacy and safety of novel anti-HBV agents. Oral administration of MIV-210 at 20 or 60 mg/kg of body weight/day induced a rapid virological response in chronically infected woodchucks, reducing serum WHV DNA levels by 4.

The design, synthesis, and antiviral activity of monofluoro and difluoro analogues of 4'-azidocytidine against hepatitis C virus replication: the discovery of 4'-azido-2'-deoxy-2'-fluorocytidine and 4'-azido-2'-dideoxy-2',2'-difluorocytidine.

The discovery of 4'-azidocytidine (3) (R1479) (J. Biol. Chem.

The design, synthesis, and antiviral activity of 4'-azidocytidine analogues against hepatitis C virus replication: the discovery of 4'-azidoarabinocytidine.

4'-Azidocytidine 3 (R1479) has been previously discovered as a potent and selective inhibitor of HCV replication targeting the RNA-dependent RNA polymerase of hepatitis C virus, NS5B. Here we describe the synthesis and biological evaluation of several derivatives of 4'-azidocytidine by varying the substituents at the ribose 2' and 3'-positions. The most potent compound in this series is 4'-azidoarabinocytidine with an IC(50) of 0.

Design, synthesis and evaluation of novel uracil acetamide derivatives as potential inhibitors of Plasmodium falciparum dUTP nucleotidohydrolase.

The ubiquitous enzyme dUTP nucleotidohydrolase (dUTPase) catalyses the hydrolysis of dUTP to dUMP and can be considered as the first line of defence against incorporation of uracil into DNA. Inhibition of this enzyme results in over-incorporation of uracil into DNA, leading to DNA fragmentation and cell death and is therefore lethal. By taking advantage of structural differences between the human and Plasmodium dUTPase, selective inhibitors of the enzyme can be designed and synthesised with the aim of being developed into novel anti-parasitic drugs.

Kinetic properties and inhibition of the dimeric dUTPase-dUDPase from Campylobacter jejuni.

The enzyme deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase) catalyses the hydrolysis of dUTP to dUMP and PPi thus controlling the incorporation of uracil into DNA genomes. In Campylobacter jejuni dUTPase exhibits structural properties of dimeric proteins characteristic of protozoa of the Kinetoplastidae family. In the present study we perform a kinetic analysis of Campylobacter dUTPase using the continuous spectrophotometric method and show that the enzyme is highly specific for deoxyuridine nucleotides.

Preclinical evaluation of 1H-benzylindole derivatives as novel human immunodeficiency virus integrase strand transfer inhibitors.

We have identified 1H-benzylindole analogues as a novel series of human immunodeficiency virus (HIV) integrase inhibitors with antiretroviral activities against different strains of HIV type 1 (HIV-1), HIV-2, and simian immunodeficiency virus strain MAC(251) [SIV(MAC(251))]. Molecular modeling and structure-activity relationship-based optimization resulted in the identification of CHI/1043 as the most potent congener. CHI/1043 inhibited the replication of HIV-1(III(B)) in MT-4 cells at a 50% effective concentration (EC(50)) of 0.

2'-deoxy-4'-azido nucleoside analogs are highly potent inhibitors of hepatitis C virus replication despite the lack of 2'-alpha-hydroxyl groups.

RNA polymerases effectively discriminate against deoxyribonucleotides and specifically recognize ribonucleotide substrates most likely through direct hydrogen bonding interaction with the 2'-alpha-hydroxy moieties of ribonucleosides. Therefore, ribonucleoside analogs as inhibitors of viral RNA polymerases have mostly been designed to retain hydrogen bonding potential at this site for optimal inhibitory potency. Here, two novel nucleoside triphosphate analogs are described, which are efficiently incorporated into nascent RNA by the RNA-dependent RNA polymerase NS5B of hepatitis C virus (HCV), causing chain termination, despite the lack of alpha-hydroxy moieties.

Acyclic nucleoside analogues as inhibitors of Plasmodium falciparum dUTPase.

We report the discovery of novel uracil-based acyclic compounds as inhibitors of deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase), an enzyme involved in nucleotide metabolism that has been identified as a promising target for the development of antimalarial drugs. Compounds were assayed against both P.falciparum dUTPase and intact parasites.

dUTPase as a platform for antimalarial drug design: structural basis for the selectivity of a class of nucleoside inhibitors.

Pyrimidine metabolism is a major route for therapeutic intervention against malaria. Here we report inhibition and structural studies on the deoxyuridine nucleotidohydrolase from the malaria parasite Plasmodium falciparum (PfdUTPase). We have identified a series of triphenylmethane derivatives of deoxyuridine with antimalarial activity in vitro which inhibit specifically the Plasmodium dUTPase versus the human enzyme.