RESUMO
The development of multistep continuous flow reactions for the synthesis of important intermediates for the pharmaceutical industry is still a significant challenge. In the present contribution the biaryl-hydrazine unit of Atazanavir, an important HIV protease inhibitor, was prepared in a three-step continuous flow sequence in 74% overall yield. The synthesis involved Pd-catalyzed SuzukiMiyaura cross-coupling, followed by hydrazone formation and a subsequent hydrogenation step, and additionally incorporates a liquidliquid extraction step.
Assuntos
Inibidores da Protease de HIV/síntese química , Oligopeptídeos/síntese química , Piridinas/síntese química , Sulfato de Atazanavir , Inibidores da Protease de HIV/química , Estrutura Molecular , Oligopeptídeos/química , Piridinas/químicaRESUMO
The mechanism of the Dakin-West reaction has been thoroughly investigated by monitoring the reaction using ESI-MS/MS techniques in combination with M06-2X/6-311++G(d,p) calculations. Several of the key intermediates in the previously proposed "azlactone" mechanism have been experimentally detected and characterized. In particular, interception of the mixed anhydrides involved in the early and late stages of the mechanistic scheme, as well as of the cyclic acyl-oxazolone intermediate, supports the original pathway suggested by Dakin and West. All intermediates and transition structures involved in several competing mechanisms have been calculated. The theoretical calculations support the experimental results and corroborate the proposed "azlactone" mechanism. The pathway involving the cyclic oxazolone ("azlactone") intermediate represents an energy barrier more than 3 kcal mol(-1) lower than for the competing aldol-type mechanism, thus ruling out this alternative mechanism. The DFT calculations explain the observed ESI-MS data and assess those intermediates which the experiments cannot fully elucidate.
Assuntos
Aminoácidos/química , Cetonas/química , Cetonas/síntese química , Teoria Quântica , Anidridos/química , Modelos Moleculares , Conformação Molecular , Oxazolona/químicaRESUMO
A series of new piperazine derivatives of ursolic acid was synthesized and tested against Plasmodium falciparum strains. They were also tested on their cytotoxicity effects upon MRC-5 cells. Seven new piperazinyl analogues showed significant activity in the nanomolar range (IC(50)=78-167nM) against Plasmodium falciparum CQ-resistant strain FcB1. A possible mechanism of interaction implicating binding of these compounds to beta-hematin was supported by in vitro tests. Moreover, the importance of the hydrophilic framework attached at the terminal nitrogen atom of the bis-(3-aminopropyl)piperazine joined to the triterpene ring was also explored through molecular dynamic simulations.
Assuntos
Antimaláricos , Piperazinas , Plasmodium falciparum/efeitos dos fármacos , Triterpenos , Animais , Antimaláricos/síntese química , Antimaláricos/química , Antimaláricos/farmacocinética , Antimaláricos/farmacologia , Técnicas de Química Combinatória , Ilex paraguariensis/química , Concentração Inibidora 50 , Estrutura Molecular , Testes de Sensibilidade Parasitária , Piperazinas/síntese química , Piperazinas/química , Piperazinas/farmacocinética , Piperazinas/farmacologia , Plantas Medicinais/química , Relação Estrutura-Atividade , Triterpenos/síntese química , Triterpenos/química , Triterpenos/farmacocinética , Triterpenos/farmacologia , Ácido UrsólicoRESUMO
A series of new ursolic and oleanolic acids derivatives was synthesized via ursolic or oleanolic acids, previously extracted from South American Ilex species. These new compounds were tested for in vitro antiparasitic activity on Leishmania amazonensis and Leishmania infantum strains. Some of these compounds showed activity against the promastigote forms of L. amazonensis or L. infantum, with IC(50) ranging from 5 to 12 microM. As expected, most of the compounds showed a significant level of cytotoxicity against monocytes (IC(50) = 2-50 microM). From a structure-activity relationships point of view, these pharmacological results enlightened mainly the importance of an acetylation at position 3 of the oleanolic acid skeleton in the activity against the L. amazonensis strain, and of a bis-(3-aminopropyl)piperazine moiety on the carboxylic function of ursolic acid against the L. infantum strain.