RESUMO
Given the rise of parasite resistance to all currently used antimalarial drugs, the identification of novel chemotypes with unique mechanisms of action is of paramount importance. Since Plasmodium expresses a number of aspartic proteases necessary for its survival, we have mined antimalarial datasets for drug-like aspartic protease inhibitors. This effort led to the identification of spiropiperidine hydantoins, bearing similarity to known inhibitors of the human aspartic protease ß-secretase (BACE), as new leads for antimalarial drug discovery. Spiropiperidine hydantoins have a dynamic structure-activity relationship profile with positions identified as being tolerant of a variety of substitution patterns as well as a key piperidine N-benzyl phenol pharmacophore. Lead compounds 4e (CWHM-123) and 12k (CWHM-505) are potent antimalarials with IC50 values against Plasmodium falciparum 3D7 of 0.310 µM and 0.099 µM, respectively, and the former features equivalent potency on the chloroquine-resistant Dd2 strain. Remarkably, these compounds do not inhibit human aspartic proteases BACE, cathepsins D and E, or Plasmodium plasmepsins II and IV despite their similarity to known BACE inhibitors. Although the current leads suffer from poor metabolic stability, they do fit into a drug-like chemical property space and provide a new class of potent antimalarial agents for further study.
Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Hidantoínas/química , Hidantoínas/farmacologia , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/metabolismo , Antimaláricos/farmacocinética , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Descoberta de Drogas , Humanos , Hidantoínas/metabolismo , Hidantoínas/farmacocinética , Malária Falciparum/parasitologia , Camundongos , Microssomos Hepáticos/metabolismo , Piperidinas/química , Piperidinas/metabolismo , Piperidinas/farmacocinética , Piperidinas/farmacologia , Plasmodium falciparum/enzimologia , Plasmodium falciparum/metabolismo , Ratos , Compostos de Espiro/química , Compostos de Espiro/metabolismo , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologiaRESUMO
An aerobic decarboxylative cross-coupling of α-amino acids with diverse C-H nucleophiles has been realized using Cu2(OH)2CO3 (1 mol%) as the catalyst under air. This protocol enables highly efficient formation of various C(sp3)-C(sp3), C(sp3)-C(sp2) and C(sp3)-C(sp) bonds under simple conditions without the use of any ligand or extra oxidant, providing a practical approach to numerous nitrogen-containing compounds in good to excellent yields. The efficiency and practicability were also demonstrated by the gram-scale experiment and three-step synthesis of a Rad51 inhibitor.
RESUMO
Given the threat of drug resistance, there is an acute need for new classes of antimalarial agents that act via a unique mechanism of action relative to currently used drugs. We have identified a set of druglike compounds within the Tres Cantos Anti-Malarial Set (TCAMS) which likely act via inhibition of a Plasmodium aspartic protease. Structure-activity relationship analysis and optimization of these aminohydantoins demonstrate that these compounds are potent nanomolar inhibitors of the Plasmodium aspartic proteases PM-II and PM-IV and likely one or more other Plasmodium aspartic proteases. Incorporation of a bulky group, such as a cyclohexyl group, on the aminohydantion N-3 position gives enhanced antimalarial potency while reducing inhibition of human aspartic proteases such as BACE. We have identified compound 8p (CWHM-117) as a promising lead for optimization as an antimalarial drug with a low molecular weight, modest lipophilicity, oral bioavailability, and in vivo antimalarial activity in mice.