RESUMEN
An enantiopure ß-lactam with a suitably disposed electron withdrawing group on nitrogen, participated in a π-allylpalladium mediated reaction with 2,6-dichloropurine tetrabutylammonium salt to afford an advanced cis-1,4-substituted cyclopentenoid with both high regio- and stereoselectivity. This advanced intermediate was successfully manipulated to the total synthesis of (-)-Abacavir.
Asunto(s)
Didesoxinucleósidos/síntesis química , Animales , Colinesterasas/metabolismo , Lipasa/metabolismo , Estructura Molecular , Pseudomonas fluorescens/enzimología , Estereoisomerismo , PorcinosRESUMEN
A series of 2-pyridyl pyrimidines, reported inhibitors of Plasmodium falciparum methionine aminopeptidase 1b were synthesized and evaluated for their antiplasmodial activities. An analysis of physicochemical properties demonstrated a link between lipophilicity and antiparasitic activity. Cross screening of the library against cultured Leishmania donovani parasites revealed this class of compounds as potent inhibitors of parasite development in vitro.
Asunto(s)
Antiprotozoarios/síntesis química , Antiprotozoarios/farmacología , Leishmania donovani/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Pirimidinas/síntesis química , Pirimidinas/farmacología , Animales , Evaluación Preclínica de Medicamentos , Relación Estructura-ActividadRESUMEN
A dual activity, conjugated approach has been taken to form hybrid molecules of two known antimalarial drugs, chloroquine (CQ) and the non-sedating H1 antagonist astemizole. A variety of linkers were investigated to conjugate the two agents into one molecule. Compounds 5-8 possessed improved in vitro activity against a CQ-resistant strain of Plasmodium falciparum, and examples 7 and 8 were active in vivo in mouse models of malaria.
Asunto(s)
Antimaláricos/química , Antimaláricos/farmacología , Astemizol/química , Cloroquina/química , Plasmodium falciparum/efectos de los fármacos , Animales , Antimaláricos/uso terapéutico , Astemizol/farmacología , Astemizol/uso terapéutico , Cloroquina/farmacología , Cloroquina/uso terapéutico , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Malaria Falciparum/tratamiento farmacológico , RatonesRESUMEN
A novel series of 4-aminoquinoline-containing 2-imidazolines were synthesized via a one-pot 3-component condensation reaction of amine, aldehyde and isocyanoacetate. The products were obtained in high yield as well as purity and were evaluated directly against two strains of Plasmodium falciparum and Trypanosoma brucei. Compound was the most active across all parasites with ED(50) = 3.3 nM against a chloroquine (CQ)-sensitive 3D7 strain, ED(50) = 33 nM against a CQ-resistant K1 strain and ED(50) = 70 nM against T. brucei. Several compounds were able to inhibit formation of beta-haematin in vitro, suggesting haemozoin formation in the malaria parasite as a possible target. On the other hand, evaluation against a human KB cell line revealed that the compounds were generally non-cytotoxic to the host cells.
Asunto(s)
Antiprotozoarios/farmacología , Antiprotozoarios/toxicidad , Diseño de Fármacos , Hemoproteínas/antagonistas & inhibidores , Imidazolinas/farmacología , Imidazolinas/toxicidad , Quinolinas/química , Animales , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Humanos , Imidazolinas/síntesis química , Imidazolinas/química , Células KB , Plasmodium falciparum/efectos de los fármacos , Trypanosoma brucei brucei/efectos de los fármacosRESUMEN
The discovery and development of novel drugs has been influenced over the last several decades by new techniques in medicinal chemistry. Combinatorial and parallel synthesis chemistry techniques have opened up immense opportunities in drug discovery and development efforts. These techniques, which include solid phase organic synthesis and polymer-assisted synthesis in solution, have been routinely applied to a number of therapeutic areas. Despite the flurry of activity that characterized small molecule drug discovery efforts in the early 1990s, it was only during the mid to late 1990s that combinatorial chemistry began to make an impact on antiparasite chemotherapy. This review focuses on the development and application of combinatorial and parallel synthesis methodologies to antiparasitic drug discovery from the mid 1990s to the end of 2002. Much of this work applies to small organic molecules as inhibitors of parasite targets although some of the early applications were to the synthesis of enzyme substrates.
Asunto(s)
Antiparasitarios/síntesis química , Antiparasitarios/farmacología , Técnicas Químicas Combinatorias/métodos , Diseño de Fármacos , Animales , HumanosRESUMEN
The presence of parasitic cysteine proteases and trypanothione reductase in the parasitic protozoa of the genus Trypanosoma and Leishmania has made these enzymes attractive targets for the development of antitrypanosomal and antileishmanial agents. Furthermore, the presence of cysteine proteases in Plasmodium falciparum has presented additional opportunities for the development of chemical scaffolds that could potentially be utilized against all of the aforementioned parasites. While previous reviews on parasitic cysteine proteases and trypanothione reductase covered various aspects, none emphasized the chemistry behind the synthesis of described inhibitors. This review focuses on recent developments in the synthesis of low-molecular weight inhibitors of these enzymes with a bearing on the human diseases of leishmaniasis, malaria and trypanosomiasis. Only those inhibitors whose synthesis has been described in the open literature during the period 1993-mid 2002 have been highlighted. The review thus excludes what may be in the patent literature. Inhibitors synthesized using combinatorial and/or parallel synthesis chemistry as well as polymer-assisted synthesis methodologies have been deliberately omitted from this review because they are a subject of a separate and focused review.
Asunto(s)
Antiprotozoarios/síntesis química , Inhibidores de Cisteína Proteinasa/síntesis química , Inhibidores Enzimáticos/síntesis química , NADH NADPH Oxidorreductasas/antagonistas & inhibidores , Animales , Antiprotozoarios/farmacología , Inhibidores de Cisteína Proteinasa/farmacología , Inhibidores Enzimáticos/farmacología , Humanos , Leishmania/efectos de los fármacos , Modelos Químicos , Estructura Molecular , Peso Molecular , Trypanosoma/efectos de los fármacosRESUMEN
The synthesis and antimalarial activity of a novel series of first generation 4-aminoquinoline-containing 2,4,5-trisubstituted aminoxazoles against two strains of the Plasmodium falciparum parasite in vitro is described. A number of compounds significantly more potent than the standard drug chloroquine were identified.
Asunto(s)
Aminoquinolinas/química , Antimaláricos/síntesis química , Antimaláricos/farmacología , Química Farmacéutica/métodos , Oxazoles/química , Plasmodium falciparum/efectos de los fármacos , Animales , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Concentración 50 Inhibidora , Pruebas de Sensibilidad Parasitaria , Plasmodium/metabolismo , Relación Estructura-ActividadRESUMEN
A parallel synthesis of a new series of 4-aminoquinoline gamma- and delta-lactams synthesized via the Ugi 3-component 4-centre multicomponent reaction is described. The basicity of the quinoline nitrogen was exploited in the purification of compounds via a 'catch and release' protocol. Yields ranging from 60% to 77% and purities as high as 96% were obtained. Compound 29, the most active against a chloroquine-resistant W2 strain of Plasmodium falciparum with an IC(50) of 0.096 microM, also inhibited recombinant falcipain-2 in vitro (IC(50)= 17.6 microM). Compound 17 inhibited the growth of Trypanosoma brucei with an ED(50) of 1.44 microM whilst exhibiting a favourable therapeutic index of 409 against a human KB cell line.
Asunto(s)
Aminoquinolinas/farmacología , Antimaláricos/farmacología , Lactamas/farmacología , Plasmodium falciparum/efectos de los fármacos , Trypanosoma brucei rhodesiense/efectos de los fármacos , Aminoquinolinas/síntesis química , Animales , Antimaláricos/síntesis química , Línea Celular , Humanos , Lactamas/síntesis química , Pruebas de Sensibilidad Parasitaria , Relación Estructura-ActividadRESUMEN
The synthesis of a new class of Ugi adducts incorporating the 4-aminoquinoline moiety is described. The novel compounds are active against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum with the best compound showing an IC(50) value of 73 nM against a resistant K1 strain.
Asunto(s)
Antimaláricos/síntesis química , Antimaláricos/farmacología , Plasmodium falciparum/efectos de los fármacos , Animales , Antimaláricos/química , Cloroquina/química , Mefloquina/química , Conformación Molecular , Estructura Molecular , Quinina/química , Relación Estructura-ActividadRESUMEN
The previously unknown antiplasmodial activity of the plant derived natural product totarol is reported. Novel beta-amino alcohol derivatives based on this natural product were designed, synthesised and evaluated for in vitro antiplasmodial activity and cytotoxicity. These derivatives showed antiplasmodial IC50 values in the range of 0.6-3.0 microM and were equally active against a chloroquine-sensitive and resistant strain of Plasmodium falciparum, while showing little cytotoxicity against a mammalian cell line (CHO). In terms of lead development, two of the compounds based on substituted phenylpiperazine warrant further investigation as potential antiplasmodial leads. In addition to their selective antiplasmodial activity and lack of chloroquine cross-resistance, these compounds are structurally different to any of the available antimalarial drugs.