Milbemycin derivaties: Modification at the C-5 position.

“…For this reason, we chose regioselective ester formation with dicarboxylic acid anhydrides at secondary 5-OH group in the presence of sterically hindered tertiary 7-OH group [11,21,22]. We have found that compounds 1a,b are rather sensitive to acidic and basic conditions that facilitate aromatization of hexahydrobenzofuran system via dehydration.…”

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confidence: 99%

“…It has been reported that naturally occurring milbemycins A 3 /A 4 , which possess antibiotic properties in a broader sense (activity against nematodes, fleas, and mites), do not act as antibacterials [11,12]. Their mode of action is connected with allosteric modulation of glutamate-gated chloride channels in roundworms and other invertebrates [13].…”

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confidence: 99%

“…It is described that compounds bearing partially lipophilic side chains arising from aromatic [18,19] and aliphatic [20] carboxylic acids show enhanced antibacterial activities. To the best of our knowledge only small amounts of such modifications have been applied on the macrolide core of milbemycins A 3 /A 4 [11,21,22] and none of the obtained compounds were tested as antibacterial agents.…”

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confidence: 99%

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Synthesis and Antibacterial Activity of 5-Phthalate and 5-Glutarate Derivatives of Milbemycins A3/A4*

Lugiņina

Bizdēna

Leončiks

et al. 2014

Chem Heterocycl Comp

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Naturally occurring 16-membered macrolides milbemycins A 3 and A 4 were selectively esterified at their 5-OH group with phthalic and glutaric anhydrides. The obtained monoesters were further functionalized by amide formation. Propargylamide derivatives were demonstrated to undergo 1,2,3-triazole formation upon treatment with organic azides in the presence of copper catalyst. Some of the synthesized compounds exhibited useful levels of antibacterial properties against Staphylococcus aureus and Staphylococcus epidermidis.Milbemycins A 3 (1a) and A 4 (1b) belong to the class of 16-membered macrolides that are produced as secondary metabolites by various Streptomyces species. Depending on the bacterial type, many milbemycin congeners and the biosynthetically related avermectins can be found in fermentation broth. These differ by substitution pattern at C-5, C-13, C-22, C-23, C-25, and C-27 atoms [1-4]. Also milbemycin A 3 differs from milbemycin A 4 by the substituent at C-25 atom -methyl and ethyl group, respectively. Over the years it was proved that both compounds possess similar biological activity profile. In order to simplify fermentation and isolation process, both natural products are used as a mixture [5]. They are known under the commercial name Milbeknock (also: Koromite, Matsuguard) as an agricultural insectoacaricide, which most often consists of a 3:7 mixture of compounds 1a and 1b [6]. Potential applications of milbemycins 1a,b in human medicine include treatment of rosacea and cancer [7,8]. Additionally, the 3:7 mixture of milbemycin A 3 and A 4 serves as the starting material for the widely used veterinary anthelmintic milbemycin oxime [9,10].

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