SYNTHESIS AND ANTI-CANDIDA ALBICANS PROPERTIES OF L-4-OXALYSINE-N³-4-METHOXYFUMAROYLL-2,3-DIAMINOPROPANOIC-CONTAINING PEPTIDE ANALOGUES

In order to improve the inhibitory activity of L-4-oxalysine(abbreviated as I-677) against clinically important pathogen Candida albicans, double warheads peptide analogues containing I-677 and N³-4-methoxyfumaroyl-L-2,3-diaminopropanoic acid( FMDP) were designed based on the concept of “Illicit Transport” and peptide transport specificities of C. albicans. One compound of I-677-FMDP and seven compounds of I-677-AA-FMDP(AA=Nva, Leu, Val, Phe, Pro, D-Pgly, D,L-p-Cl-Phe) were synthesized and examined for antifungal activities. The results of antiCandida albicans test in vitro of these double warheads peptide analogues containing I-677 and FMDP showed very high activities against Candida albicans. The molar MIC(molar minimum inhibitory concentration) ratio of free I-677 to I-677-AA-FMDP is 40～770 and that of FMDP is 60～1130. The values of molar MIC of I-677-AA-FMDP varied from 6.56×10^-9 mol·disk^-1 to 3.5×10^-10　mol·disk^-1. The results of competitive antagonism studies indicated that I-677-AA-FMDP were transported into Candida albicans cells by the ditripeptide permease and subsequently hydrolyzed by intracellular peptidases, releasing free I-677 and FMDP inside cells. The result of antienzymic degradation test in vitro of I-677-FMDP showed that compound I-677-FMDP was resistant to the hydrolysis by carboxypeptidase A.