ABSTRACT
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.
Subject(s)
HIV Protease Inhibitors/chemical synthesis , Oligopeptides/chemical synthesis , Pyridines/chemical synthesis , Atazanavir Sulfate , HIV Protease Inhibitors/chemistry , Molecular Structure , Oligopeptides/chemistry , Pyridines/chemistryABSTRACT
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.
Subject(s)
Amino Acids/chemistry , Ketones/chemistry , Ketones/chemical synthesis , Quantum Theory , Anhydrides/chemistry , Models, Molecular , Molecular Conformation , Oxazolone/chemistryABSTRACT
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.
Subject(s)
Antiprotozoal Agents/chemical synthesis , Leishmania/drug effects , Oleanolic Acid/pharmacology , Triterpenes/pharmacology , Animals , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Humans , Inhibitory Concentration 50 , Leishmania infantum/drug effects , Leishmania mexicana/drug effects , Monocytes/drug effects , Oleanolic Acid/chemical synthesis , Oleanolic Acid/chemistry , Structure-Activity Relationship , Triterpenes/chemical synthesis , Triterpenes/chemistry , Ursolic AcidABSTRACT
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.