Semisynthetic Coumermycins: Structure-Activity Relationships

Abstract

The relative antimicrobial activity of a large series of semisynthetic coumermycins has been determined. Most of the derivatives, which were 3-substituted-4-hydroxy-8-methyl-7-[3-O-(5-methyl-2-pyrrolylcarbonyl) noviosyloxy] coumarins, had an in vitro antibacterial spectrum similar to that of the parent compound, coumermycin A 1 , but were generally less potent in minimal inhibitory concentration (MIC) tests. Derivatives with an alkylcarboxamido, arylcarboxamido, or arylsulfonamido group in the 3 position had considerably greater in vitro activity than those possessing an amino-, aryl-, or alkyureido substituent. Efficacy in Staphylcoccous aureus Smith infections of mice was greater for those compounds with branched-chain alkylcarboxamido, unsubstituted, mono- or disubstituted aryl- and heteroaryl-carboxamido groups than for derivatives having an n -alkylcarboxamido, aralkyl-carboxamido, arylsulfonamido, or trisubstituted arylcarboxamido substituent. Significant in vitro activity against Klebsiella pneumoniae and other gram-negative species was restricted to those compounds having a 3-(3- n -alkyl-4-hydroxy-phenyl-carboxamido) group. Only the n -hexyl homologue demonstrated in vivo activity in a K. pneumoniae infection. Many derivatives were two- to threefold more active than coumermycin A 1 in orally treated mouse infections, despite the fact that their MIC values were considerably higher. This result was undoubtedly a reflection of the markedly greater oral absorbability possessed by many of the derivatives. Although peak oral mouse blood levels of some compounds were > 25 times higher than those of coumermycin A 1 , their toxicity for the host was no greater. In addition, the semisynthetic coumermycins caused much less local irritation than coumermycin A 1 when administered parenterally.

Non-quinolone Inhibitors of Bacterial Type IIA Topoisomerases: A Feat of Bioisosterism

“…185,186 However, the strong serum binding of this large molecule has been advanced as the cause of its lack of effect in vivo. 187 Extensive studies of the antibacterial mechanism of action of novobiocin (1) and coumermycin A1 (9) demonstrated that they inhibit DNA gyrase and topoisomerase IV by binding to the ATPase domain of GyrB and ParE subunits, respectively. 7,8,70,181,188−190 A third naturally occurring coumarin, clorobiocin (10), features a structure closely related to novobiocin (1) but for a pyrrole moiety replacing the carbamate group and a chlorine atom instead of a methyl.…”

“…Moreover, the many effects of novobiocin ( 1 ) in models of biochemical processes, such as histone precipitation, inhibition of yeast glycyl- and leucyl-tRNA synthetases, eukaryotic topoisomerases, or HSP90, probably explain the eukaryotic toxicity of such compounds . Coumermycin ( 9 ) was also the subject of studies across the years as it demonstrated potentially useful activity in vitro. , However, the strong serum binding of this large molecule has been advanced as the cause of its lack of effect in vivo . Extensive studies of the antibacterial mechanism of action of novobiocin ( 1 ) and coumermycin A1 ( 9 ) demonstrated that they inhibit DNA gyrase and topoisomerase IV by binding to the ATPase domain of GyrB and ParE subunits, respectively. ,,,,− A third naturally occurring coumarin, clorobiocin ( 10 ), features a structure closely related to novobiocin ( 1 ) but for a pyrrole moiety replacing the carbamate group and a chlorine atom instead of a methyl.…”

Phenomena and Mechanism for Separation and Recovery of Penicillin in Ionic Liquids Aqueous Solution

“…Although some ATP systems using temperature-sensitive surfactant or polymer were reported to solve this problem, 12.20 it is primarily suitable for nonpolar solute. When high efficiency is desired for polar solutes, a certain amount of ionic surfactant has to be added, , which unfavorably increases the cloud-point temperature and leads to low stability of penicillin at this temperature …”