Mannich Ketones as Possible Antimycobacterial Agents

Twenty‐three known unsaturated and fused Mannich ketones and their reduced derivatives (amino alcohols) were selected for an antituberculotic study. They were screened against several mycobacterial strains including Mycobacterium tuberculosis, M. xenopi, and M. gordonae, and minimum inhibitory concentration values were also determined using the standard antituberculotic drug isoniazid (INH) as a reference. Structure–activity relationships were also studied. The mode of action of the test compounds was investigated using transmission electron microscopy, high‐performance liquid chromatography, and matrix‐assisted desorption/ionization mass spectrometry. Several test substances proved to be as potent as INH, but their antimycobacterial spectra were broader than that of INH. Our findings suggest that their mode of action is probably through the inhibition of mycobacterial cell wall biosynthesis. The antimycobacterial activities of (E)‐2‐phenylmethylene‐6‐morpholin‐1‐ylmethyl‐cyclohexanone (1), cis‐(E)‐2‐phenylmethylene‐6‐morpholin‐1‐ylmethyl‐cyclohexanol (8) and trans‐(E)‐2‐phenylmethylene‐6‐morpholin‐1‐ylmethyl‐cyclohexanol (9) are compared. Compound 1 is a ketone with a MIC value of 100 µg/mL against the standard Mycobacterium tuberculosis H37Rv strain, while the aminoalcohols 8 and 9 were more efficient (MIC: 12.5 µg/mL). The test compounds may interfere with mycolic acid biosynthesis.
Source: Archiv der Pharmazie - Category: Drugs & Pharmacology Authors: Tags: Full Paper Source Type: research