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Several series of pseudomonic acid analogues have been prepared that incorporate modified functionalities in place of the C1-C3 alpha,beta-unsaturated ester group. The inhibition of isoleucyl-tRNA synthetase and the in vitro activity of these compounds against various Gram-positive and Gram-negative strains are described. Several derivatives showed enzyme inhibition equivalent to or better than that of methyl pseudomonate (3), while lacking the hydrolyzable ester group at C1. These analogues include the corresponding phenyl ketone and the ether 12. The long-chain ketone 24 exhibited similar in vitro activity as the parent ester.

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One of the major disadvantages of the antibiotic erythromycin A is the poor pharmacokinetic profile caused by its acid instability. Under low pH conditions, the formation of the relatively inactive 6,9-enol ether 1 and 6,9-9,12 spiroketal 2 occurs* 1 (Scheme I), and many attempts at avoiding this degradative process through modification of the C-9 carbonyl center or blocking of the C-6 hydroxyl have been pursued.2 In this paper we report our synthesis of 9(fi)-dihydro-6,9-anhydroerythromycin A (4) and other 6,9-linked analogs which should have increased acid stability as compared to erythromycin A.The 6,9-ether structure was targeted since modeling studies predicted conservation of the structural integrity of the lactone and pendant sugars. Our first approach involved the catalytic hydrogenation of erythromycin A enol ether and was initially carried out as per the reduction by Kurath3 of the enol ether of erythronolide B. Under'