Synthesis, Conformational Analysis, and Evaluation of 6R- and 6S‑Methylmannoimidazoles as Mannosidase Inhibitors.

Extrapolating from earlier studies in which it was shown that 6S-methyl-1-deoxymannojirimycin was a more potent inhibitor of the Bacteroides thetaiotaomicron mannosidase BtMan2A than either its 6R-isomer or the parent 1-deoxymannojirimycin, the corresponding 6R- and 6S-methylmannoimidazole-type inhibitors were prepared along with mannoimidazole itself and screened for inhibition of BtMan2A and two further mannosidases: Bt3990 and Bt3965. As expected, for each of the three enzymes, 6S-methylmannoimidazole was a better inhibitor than its 6R-isomer, but it was less potent than the parent unsubstituted mannoimidazole. A combined coupling constant and nuclear Overhauser effect study revealed that the inclusion of the additional methyl group in the side chain of methylmannoimidazole results in changes in the side chain and ring conformation owing to isomer-dependent steric clashes between either the side chain alcohol or the methyl group and the imidazole H7, which ultimately are responsible for destabilization of complexes with the active sites of the mannosidases.