New Bis(2-aminoimidazoline) and Bisguanidine DNA Minor Groove Binders with Potent in Vivo Antitrypanosomal and Antiplasmodial Activity

Abstract

a Abbreviations: CQ = chloroquine; FACS = Fluorescence-activated cell sorting; FPIX = ferriprotoporphyrin IX; HEPES = 4-(2-hydroxyethyl)-1-piperazinethanesulfonic acid; MEM = minimum essential medium; MOA = mechanism of action; µCi = microCurie; Pip = piperidine; SI = selectivity index.

Antiprotozoal activity and DNA binding of N-substituted N-phenylbenzamide and 1,3-diphenylurea bisguanidines

“…The mice that survived 60 days free of parasites were considered as cured ( Table 1). were all positive at day 7. g Data previously reported in reference [11] and shown here for comparative purpose. h Not determined.…”

“…The choice of these scaffolds as antitrypanosomal templates was also supported by the excellent results obtained with bis (2-aminoimidazoline) analogues that proved to be 100% curative in vivo in the STIB900 mouse model [11]. (I) and 1,3-Diphenylurea (II) Bisguanidinium Leads [11] In previous work, Arafa et al [15] showed that N-alkyl derivatives of diguanidino fused ring systems had improved in vivo potency in the STIB900 mouse model of acute HAT compared with the unsubstituted diguanidino parent compounds. In the present study, we tested a similar strategy with the hits I and II to check if the antiprotozoan activity of these hits could be enhanced in that way.…”

“…Dicationic compounds such as diamidines [7][8][9][10] and bis(2-aminoimidazolines) [11][12][13] have a track record of success as antiprotozoan agents. These compounds bind strongly to the DNA minor groove at AT-rich sites which is one of the known targets of these molecules.…”

“…Accordingly dicationic diamidines were shown to be localized to the DNAcontaining nucleus and/or kinetoplast of trypanosomes [14]. Bisguanidine related molecules are also very active against T. brucei and P. falciparum [11][12][13][15][16][17][18][19].…”

“…In recent years, we have discovered a set of bisguanidinium hits that displayed excellent activities in vitro against T. b. rhodesiense and P. falciparum [11]. Two hit compounds derived from the N-phenylbenzamide scaffold (I) and the 1,3-diphenylurea scaffold (II)…”