Design, synthesis, and evaluation of l-cystine diamides as l-cystine crystallization inhibitors for cystinuria

Abstract To overcome the chemical and metabolic stability issues of l -cystine dimethyl ester (CDME) and l -cystine methyl ester (CME), a series of l -cystine diamides with or without N α -methylation was designed, synthesized, and evaluated for their inhibitory activity of l -cystine crystallization. l -Cystine diamides 2a – i without N α -methylation were found to be potent inhibitors of l -cystine crystallization while N α -methylation of l -cystine diamides resulted in derivatives 3b – i devoid of any inhibitory activity of l -cystine crystallization. Computational modeling indicates that N α -methylation leads to significant decrease in binding of the l -cystine diamides to l -cystine crystal surface. Among the l -cystine diamides 2a – i , l -cystine bismorpholide (CDMOR, LH707, 2g ) and l -cystine bis( N′ -methylpiperazide) (CDNMP, LH708, 2h ) are the most potent inhibitors of l -cystine crystallization.