Synthesis and biological evaluation of bisphosphonates derivatives as potent inhibitors of T. cruzi proliferation

GARCÍA LIÑARES, GUADALUPE; RODRIGUEZ, JUAN BAUTISTA

São Pedro, San Pablo, Brasil

Congreso; 13th Brazilian Meeting on Organic Synhesis; 2009

Brazilian Chemical Society

The existing chemotherapy for American trypanosomiasis or Chagas´ disease is not satisfactory in terms of its lack of effectiveness, the toxicity associated to long-term treatments and different strain sensitivity to the available drugs. Bisphosphonates derivatives exhibit valuable pharmacological actions These compounds have been used in bone disorders1 and, recently, some derivatives proved to be potent growth inhibitors of T. cruzi in vitro and in vivo without toxicity to the host cells. In order to develop new chemotherapy, we have designed ans synthesized novel bisphosphonates derivatives. Bisphosphonates derived from fatty acids, were shown to be potent growth inhibitors against the clinically more relevant form of T. cruzi.2 Compound 1 arises as main member of this new family of drugs being farnesyl diphosphate synthase (TcFPPS) the molecular target. In addition, we have recently proved that 2-alkylaminoethyl-1,1-bisphosphonic acids were of great effectiveness against both T. cruzi and the target enzyme TcFPPS.3 Bearing in mind that bisphosphonate tridentate coordinate Mg+2 at the active site of TcFPPS and also the ability of the residue of Asp250 to form a hydrogen bond with bisphosphonate inhibitors bearing a suitable group at the C-1 position, it is of interest further studies about the influence of different groups that were capable of forming hydrogen bonds. Therefore, a fluorine atom would seem to be appropriate isosteric replacement of the hydroxyl group.  1-Fluor-1,1-bisphosphonic acids (4) were straightforwardly prepared as illustrated in the Scheme 1. Compound 3 was prepared from bisphosphonate 2 according to a slightly modified Degenhart protocol. Then, 3 was reacted with Grignard reagents in a Michael-type reaction to afford the respective Michael adducts, which were treated with NaH / selectfluor. The synthetic intermediates were hydrolyzed by treatment with concentrated hydrochloric acid to afford compounds 4. Compounds of general formula 4 were successfully obtained using Grignard reagents with R from methyl to n-decyl. The biological activity as growth inhibitors against the amastigote form of T. cruzi and as inhibitors of TcFPPS activity of these 1-fluor-1,1-bisphosphonic acids is currently being evaluated. As bisphosphonate-containing compounds are FDA-approved drugs for the treatment of bone resorption disorders, their potential low toxicity makes them good candidates to control tropical diseases