Several structural analogs of putative tetrahedral intermediates of the reaction catalysed by the glutamine amide transfer domain of Candida albicans glucosamine 6-phosphate synthase have been designed and synthesized. Esters and amides of gamma-phosphonic and gamma-sulfonic analogs of glutamine and glutamic acid were tested as potential inhibitors of the enzyme. N-substituted amides 9 and 15 were found to be the strongest inhibitors in the series. Structure-activity relationship studies led to conclusions supporting the possibility of a direct nucleophilic attack of the glutamine amide nitrogen on an electrophilic site of the enzyme-bound fructose 6-phosphate as the most likely mechanism of nitrogen transfer in glucosamine 6-phosphate synthase. (C) 1997 Academic Press.