Synthesis of 5-Keto-5-oxime Derivatives of Milbemycins and Their Activities against Microfilariae.

Abstract

Starting from milbemycin D (1), milbemycin A4 (2) and milbemycin A3 (3), a series of 5-keto-5-oxime derivatives were synthesized by selective oximation at the a,/?-conjugated carbonyl function of the 5-ketomilbemycins (4-6). The activities of the synthesized compoundswere studied in dogs naturally infested with microfilariae of Dirofilaria immitis. The 5-keto-5-oximes of milbemycin D (7), A4 (8) and A3 (9) had quite high efficacy to control the microfilariae and more potency than their parents, while the 5-O-acyl oximes (ll-15) also exhibited high activity. The synthesis of the 5-keto-5-oxime derivatives is shown in Scheme 1. The 5-keto intermediates ofmilbemycin A3 (6) and A4 (5) were also isolated from a culture broth of Streptomyces hygroscopicus, and were named 2615 milbemycin J and K, respectively

New 5-oxomilbemycins from a Genetically Engineered Strain Streptomyces bingchenggensis BCJ60

“…The relative configuration of 1 was assigned as occurring with 5-oxomilbemycins A3/A4. (Table 1) [7][8][9] showed a close similarity, except for the absence of a methine group (C-2 in 5-oxomilbemycin A4) in 2. Instead, an oxygenated quaternary carbon (δ C 75.0, C-2) was observed in 2.…”

“…The LC 50 s of tested compounds were calculated using the probit method. Table 1 and revealed compound 1 possessed the same macrocyclic lactone skeleton as 5-oxomilbemycin A3 (milbemycin J) [7][8][9] and milbemycin β 12 [10]. Differences between compound 1 and 5-oxomilbemycin A3 were that the furan ring was missing and instead a C-27 aldehyde group was present in 1.…”

“…Currently, milbemycin oxime is synthesized by a two-step chemical reaction, which involves the ketonization of milbemycins A3/A4 to yield the intermediates 5-oxomilbemycins A3/A4 with chromicanhydride as catalyst [4]. Due to the low efficiency and environmental unfriendliness of the ketonization of milbemycins A3/A4, it is imperative to develop alternative strategies to produce 5-oxomilbemycins A3/A4.…”

Synthesis of 24a-Substituted Milbemycin A4 Derivatives and Their Acaricidal Activity against Tetranychus uvticae

“…All new compounds were characterized by their NMR, IR, and mass spectral data and by high-resolution mass spectra. (3) with pivaloyl chloride to give 24a-pivaloyloxymilbemycin A4 (4) and 5-0-pivaloyl-24a-pivaloyloxymilbemycin A4 (5). To a solution of 3 (112 mg) in dichloromethane (5 ml) in an ice bath were added pyridine (32 pJ) and pivaJoyl chloride (49 .ul).…”

“…In the wake of this, a mixture of 5-deoxy-5-oxomilbemycin A3 5-oxime (Id) and 5-deoxy-5-oxomilbemycin A4 5-oxime (1e) has also been launched as a parasiticide for dogs. 3 ) Avermectins 2, which have a similar structure to milbemycins, have also shown potent and diverse activities as anthelmintics, acaricides, and insecticides 4 ) (Scheme 1).…”