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A series of novel quinolin-4-yloxy-α-hydroxy-β-amino acids were synthesized and evaluated for in vitro antimycobacterial activity. The activities of the title compounds were tested against both drug-susceptible and multidrug-resistant Mycobacterium tuberculosis. SAR studies showed that substitution at the N(4) position of quinolin-4-yloxy-α-hydroxy-β-amino acids afforded compounds with decreased in vitro antimycobacterial activity against M. tuberculosis H37Rv and H37Ra. Interestingly, compounds 6 and 17, bearing pyrazole ring, exhibited extremely good activities against both drug-sensitive and multidrug-resistant M. tuberculosis strains with MIC values in the low μM range. Moreover, these two most active compounds 17 and 6 showed favorable selectivity index values against M. tuberculosis H37Ra (5.4 and 2.3, respectively). Further, in vitro metabolic stability studies of 17 and 6 in human liver microsomes with and without NADPH, as well as their in vivo excretion profiles in Sprague-Dawley rats were conducted. Compound 6 was found to be more stable to metabolism in human microsomes and more rapidly excreted by rats when compared to compound 17. However, drug-drug interaction studies showed that co-administration of 26 with rifampicin, a clinical regimen for antituberculosis therapy, resulted in an increase in the plasma concentrations of 26, suggesting an inhibition of 26 metabolism by rifampicin.Q:
How to use a UDF inside mapreduce and is it a good idea to use one?
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