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2.
J Med Chem ; 60(16): 6880-6896, 2017 08 24.
Article in English | MEDLINE | ID: mdl-28806082

ABSTRACT

Since the appearance of resistance to the current front-line antimalarial treatments, ACTs (artemisinin combination therapies), the discovery of novel chemical entities to treat the disease is recognized as a major global health priority. From the GSK antimalarial set, we identified an aminoxadiazole with an antiparasitic profile comparable with artemisinin (1), with no cross-resistance in a resistant strains panel and a potential new mode of action. A medicinal chemistry program allowed delivery of compounds such as 19 with high solubility in aqueous media, an acceptable toxicological profile, and oral efficacy. Further evaluation of the lead compounds showed that in vivo genotoxic degradants might be generated. The compounds generated during this medicinal chemistry program and others from the GSK collection were used to build a pharmacophore model which could be used in the virtual screening of compound collections and potentially identify new chemotypes that could deliver the same antiparasitic profile.


Subject(s)
2,2'-Dipyridyl/analogs & derivatives , Antimalarials/pharmacology , Oxadiazoles/pharmacology , 2,2'-Dipyridyl/administration & dosage , 2,2'-Dipyridyl/chemical synthesis , 2,2'-Dipyridyl/pharmacology , 2,2'-Dipyridyl/toxicity , Animals , Antimalarials/administration & dosage , Antimalarials/chemical synthesis , Antimalarials/toxicity , Atovaquone/pharmacology , Chloroquine/pharmacology , Drug Design , Female , Humans , Hydrazines/metabolism , Mice , Mutagenicity Tests , Mutagens/metabolism , Oxadiazoles/administration & dosage , Oxadiazoles/chemical synthesis , Oxadiazoles/toxicity , Parasitemia/drug therapy , Plasmodium falciparum/drug effects , Pyrimethamine/pharmacology , Structure-Activity Relationship
3.
PLoS Negl Trop Dis ; 11(5): e0005629, 2017 May.
Article in English | MEDLINE | ID: mdl-28542202

ABSTRACT

In recent years, the neglected diseases drug discovery community has elected phenotypic screening as the key approach for the identification of novel hit compounds. However, when this approach is applied, important questions related to the mode of action for these compounds remain unanswered. One of such questions is related to the rate of action, a useful piece of information when facing the challenge of prioritising the most promising hit compounds. In the present work, compounds of the "Leishmania donovani box" were evaluated using a rate of action assay adapted from a replicative intracellular high content assay recently developed. The potency of each compound was determined every 24 hours up to 96 hours, and standard drugs amphotericin B and miltefosine were used as references to group these compounds according to their rate of action. Independently of this biological assessment, compounds were also clustered according to their minimal chemical scaffold. Comparison of the results showed a complete correlation between the chemical scaffold and the biological group for the vast majority of compounds, demonstrating how the assay was able to bring information on the rate of action for each chemical series, a property directly linked to the mode of action. Overall, the assay here described permitted us to evaluate the rate of action of the "Leishmania donovani box" using two of the currently available drugs as references and, also, to propose a number of fast-acting chemical scaffolds present in the box as starting points for future drug discovery projects to the wider scientific community. The results here presented validate the use of this assay for the determination of the rate of action early in the discovery process, to assist in the prioritisation of hit compounds.


Subject(s)
Amphotericin B/pharmacology , Antiprotozoal Agents/pharmacology , Drug Evaluation, Preclinical/methods , Leishmania donovani/drug effects , Macrophages/parasitology , Phosphorylcholine/analogs & derivatives , Cell Line, Tumor , Humans , Leishmaniasis, Visceral/drug therapy , Phosphorylcholine/pharmacology
4.
J Med Chem ; 59(11): 5416-31, 2016 06 09.
Article in English | MEDLINE | ID: mdl-27127993

ABSTRACT

Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher metabolic clearance than 1, they most likely would need to be part of a multidose regimen.


Subject(s)
Antimalarials/pharmacology , Enzyme Inhibitors/pharmacology , Malaria, Falciparum/drug therapy , Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , Plasmodium falciparum/drug effects , Pyrimidines/pharmacology , Triazoles/pharmacology , Animals , Antimalarials/chemical synthesis , Antimalarials/chemistry , Dihydroorotate Dehydrogenase , Disease Models, Animal , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Mice , Mice, SCID , Molecular Structure , Oxidoreductases Acting on CH-CH Group Donors/metabolism , Parasitic Sensitivity Tests , Plasmodium falciparum/enzymology , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistry
5.
Antimicrob Agents Chemother ; 60(6): 3524-32, 2016 06.
Article in English | MEDLINE | ID: mdl-27021313

ABSTRACT

The protozoan parasite Leishmania donovani is the causative agent of visceral leishmaniasis, a disease potentially fatal if not treated. Current available treatments have major limitations, and new and safer drugs are urgently needed. In recent years, advances in high-throughput screening technologies have enabled the screening of millions of compounds to identify new antileishmanial agents. However, most of the compounds identified in vitro did not translate their activities when tested in in vivo models, highlighting the need to develop more predictive in vitro assays. In the present work, we describe the development of a robust replicative, high-content, in vitro intracellular L. donovani assay. Horse serum was included in the assay media to replace standard fetal bovine serum, to completely eliminate the extracellular parasites derived from the infection process. A novel phenotypic in vitro infection model has been developed, complemented with the identification of the proliferation of intracellular amastigotes measured by EdU incorporation. In vitro and in vivo results for miltefosine, amphotericin B, and the selected compound 1 have been included to validate the assay.


Subject(s)
Amphotericin B/pharmacology , Antiprotozoal Agents/therapeutic use , Drug Evaluation, Preclinical/methods , Leishmania donovani/growth & development , Leishmaniasis, Visceral/drug therapy , Phosphorylcholine/analogs & derivatives , Animals , Cell Line, Tumor , Female , Humans , Leishmania donovani/drug effects , Macrophages/parasitology , Mice , Mice, Inbred BALB C , Parasitic Sensitivity Tests , Phosphorylcholine/pharmacology
6.
ACS Med Chem Lett ; 5(6): 657-61, 2014 Jun 12.
Article in English | MEDLINE | ID: mdl-24944739

ABSTRACT

Antiparasitic oral drugs have been associated to lipophilic molecules due to their intrinsic permeability. However, these kind of molecules are associated to numerous adverse effects, which have been extensively studied. Within the Tres Cantos Antimalarial Set (TCAMS) we have identified two small, soluble and simple hits that even presenting antiplasmodial activities in the range of 0.4-0.5 µM are able to show in vivo activity.

7.
J Med Chem ; 54(15): 5540-61, 2011 Aug 11.
Article in English | MEDLINE | ID: mdl-21696174

ABSTRACT

Drug therapy is the mainstay of antimalarial therapy, yet current drugs are threatened by the development of resistance. In an effort to identify new potential antimalarials, we have undertaken a lead optimization program around our previously identified triazolopyrimidine-based series of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. The X-ray structure of PfDHODH was used to inform the medicinal chemistry program allowing the identification of a potent and selective inhibitor (DSM265) that acts through DHODH inhibition to kill both sensitive and drug resistant strains of the parasite. This compound has similar potency to chloroquine in the humanized SCID mouse P. falciparum model, can be synthesized by a simple route, and rodent pharmacokinetic studies demonstrated it has excellent oral bioavailability, a long half-life and low clearance. These studies have identified the first candidate in the triazolopyrimidine series to meet previously established progression criteria for efficacy and ADME properties, justifying further development of this compound toward clinical candidate status.


Subject(s)
Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , Pyrimidines/chemistry , Triazoles/chemistry , Animals , Antimalarials/chemical synthesis , Antimalarials/pharmacology , Chemical Phenomena , Crystallography, X-Ray , Dihydroorotate Dehydrogenase , Drug Resistance , Humans , Mice , Plasmodium falciparum/enzymology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/pharmacokinetics , Triazoles/pharmacology
8.
J Med Chem ; 53(16): 6129-52, 2010 Aug 26.
Article in English | MEDLINE | ID: mdl-20672841

ABSTRACT

Falcipain-2 and falcipain-3 are papain-family cysteine proteases of the malaria parasite Plasmodium falciparum that are responsible for host hemoglobin hydrolysis to provide amino acids for parasite protein synthesis. Different heteroarylnitrile derivatives were studied as potential falcipain inhibitors and therefore potential antiparasitic lead compounds, with the 5-substituted-2-cyanopyrimidine chemical class emerging as the most potent and promising lead series. Through a sequential lead optimization process considering the different positions present in the initial scaffold, nanomolar and subnanomolar inhibitors at falcipains 2 and 3 were identified, with activity against cultured parasites in the micromolar range. Introduction of protonable amines within lead molecules led to marked improvements of up to 1000 times in activity against cultured parasites without noteworthy alterations in other SAR tendencies. Optimized compounds presented enzymatic activities in the picomolar to low nanomolar range and antiparasitic activities in the low nanomolar range.


Subject(s)
Antimalarials/chemical synthesis , Cysteine Endopeptidases/metabolism , Cysteine Proteinase Inhibitors/chemical synthesis , Protozoan Proteins/metabolism , Antimalarials/chemistry , Antimalarials/pharmacology , Cysteine Endopeptidases/chemistry , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/pharmacology , Plasmodium falciparum/drug effects , Plasmodium falciparum/enzymology , Protozoan Proteins/chemistry , Recombinant Proteins/chemistry , Structure-Activity Relationship
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