New Pyrrolo-quinoxaline Derivatives:Synthesis, And In Vitro Antimalarial Activity

Therapy of patients with malaria is still a serious problem. Thus, present chemotherapies are proving inadequate, are toxic, or are becoming ineffective due to an increase in resistance. Chloroquine is, after50years, still a mainstream drug in the fight against malaria, but its efficacy is being steadily eroded by the development of resistant parasites. Nowadays, there is an urgent need for the discovery and the development of new, efficient, and safe drugs for the treatment of this disease. For several years, it was proposed a strategy for the development of organometallic-based antimalarial drugs. Ferrocene and its derivatives behaved many special properties and they have been used in many areas, such as catalysis, electrochemistry, assistant combustion reagents, medicine, et al. Given the avidity of Plasmodium for free iron, it was postulated that an effective way of removing the chloroquine resistance of parasites might be the addition of iron to a chloroquine molecule and that a ferrocene moiety will permit to vectorize the drug to the selected target. Hence, some new organometallic compounds including a ferrocene nucleus (dicyclopentadienyl iron) incorporated on many medicine were designed, which led to the discovery of ferroquine, ferrocene-derived artemisinins, ferrocenyl atovaquone analogues or ferrocenyl ciprofloxacin derivatives.In the course of our work devoted to discover new compounds employed in the antimalarial chemotherapy. Thus, taking into account our experience in the field of the synthesis of new bioactive heterocyclic compounds based on pyrrolo[1,2-a]-quinoxaline heterocyclic core, we used the pyrrolo[1,2-a]quinoxaline moiety as a template for the design of new derivatives in which the ferrocene nucleus is directly incorporated in position3of the heterocyclic core. The new ferrocenic pyrrolo[1,2-a]-quinoxaline derivatives1a-1, and2a-b were both synthesized from commercially available ferrocene-carboxaldehyde. Novel series of ferrocenyl substituted pyrrolo[1,2-a]quinoxalines1-2were synthesized from ferrocene-carboxaldehyde in6or9steps.We tested all products for their in vitro activity upon the erythrocytic development of Plasmodium falciparum strains with different chloroquine-resistance status. The ferrocenic pyrrolo[1,2-a]quinoxalines1-2were prepared through a Barton-Zard reaction. Promising pharmacological results against FcB1, K1and F32 strains were obtained with ferrocenylpyrrolo[1,2-a]quinoxalines linked by a bis-(3-aminopropyl)piperazine linker substituted by a nitrobenzyl moiety. These results clearly indicate that the choice and the substitution of the terminal benzyl in the bis(3-aminopropyl)piperazine linker of the ferrocenyl pyrrolo[1,2-a]quinoxaline moiety correlated with a particular lipophilic behavior seem to be fundamental for the antimalarial activity observed for this new series. A series of target Compounds which were synthesized during the experiment, are characterized the structure by using1H NMR,13C NMR, mass spectra (MS), and infrared spectra (IR) techniques.