Synthesis of 6″-Modified Kanamycin A Derivatives and Evaluation of Their Antibacterial Properties.

Aminoglycosides are one of the first classes of antibiotics to have been used clinically, and they are still being used today. They have a broad spectrum of antimicrobial activity, making them effective against many different types of bacteria. Despite their long history of use, aminoglycosides are still considered promising scaffolds for the development of new antibacterial agents, particularly as bacteria continue to develop resistances to existing antibiotics. We have synthesized a series of 6″-deoxykanamycin A analogues with additional protonatable groups (amino-, guanidino or pyridinium) and tested their biological activities. For the first time we have demonstrated the ability of the tetra-N-protected-6″-O-(2,4,6-triisopropylbenzenesulfonyl)kanamycin A to interact with a weak nucleophile, pyridine, resulting in the formation of the corresponding pyridinium derivative. Introducing small diamino-substituents at the 6″-position of kanamycin A did not significantly alter the antibacterial activity of the parent antibiotic, but further modification by acylation resulted in a complete loss of the antibacterial activity. However, introducing a guanidine residue led to a compound with improved activity against S. aureus. Moreover, most of the obtained 6″-modified kanamycin A derivatives were less influenced by the resistant mechanism associated with mutations of the elongation factor G than the parent kanamycin A. This suggests that modifying the 6″-position of kanamycin A with protonatable groups is a promising direction for the further development of new antibacterial agents with reduced resistances.

Semisynthetic Amides of Amphotericin B and Nystatin A1: A Comparative Study of In Vitro Activity/Toxicity Ratio in Relation to Selectivity to Ergosterol Membranes.

Polyene antifungal amphotericin B (AmB) has been used for over 60 years, and remains a valuable clinical treatment for systemic mycoses, due to its broad antifungal activity and low rate of emerging resistance. There is no consensus on how exactly it kills fungal cells but it is certain that AmB and the closely-related nystatin (Nys) can form pores in membranes and have a higher affinity towards ergosterol than cholesterol. Notably, the high nephro- and hemolytic toxicity of polyenes and their low solubility in water have led to efforts to improve their properties. We present the synthesis of new amphotericin and nystatin amides and a comparative study of the effects of identical modifications of AmB and Nys on the relationship between their structure and properties. Generally, increases in the activity/toxicity ratio were in good agreement with increasing ratios of selective permeabilization of ergosterol- vs. cholesterol-containing membranes. We also show that the introduced modifications had an effect on the sensitivity of mutant yeast strains with alterations in ergosterol biosynthesis to the studied polyenes, suggesting a varying affinity towards intermediate ergosterol precursors. Three new water-soluble nystatin derivatives showed a prominent improvement in safety and were selected as promising candidates for drug development.

Semisynthetic Amides of Polyene Antibiotic Natamycin.

Natamycin is a macrolide polyene antibiotic, characterized by a potent broad spectrum antifungal activity and low toxicity. However, it is not used for the treatment of systemic mycoses due to its low bioavailability and low solubility in aqueous solutions. In order to create new semisynthetic antifungal agents for treatment of mycoses, a series of water-soluble amides of natamycin were synthesized. Antifungal activities of natamycin derivatives were investigated against Candida spp., including a panel of Candida auris clinical isolates and filamentous fungi. Toxicity for mammalian cells was assayed by monitoring antiproliferative activity against human postnatal fibroblasts (HPF) and human embryonic kidney cells (HEK293). By comparing leakage of contents from ergosterol versus cholesterol containing vesicles, a ratio that characterizes the efficacy and safety of natamycin and its derivatives was determined (EI, efficiency index). Ability of all tested semisynthetic natamycines to prevent proliferation of the yeast Candida spp. cells was comparable or even slightly higher to those of parent antibiotic. Interestingly, amide 8 was more potent than natamycin (1) against all tested C. auris strains (MIC values 2 µg/mL vs 8 µg/mL, respectively). Among 7 derivatives, amide 10 with long lipophilic side chains showed the highest EI and strong antifungal activity in vitro but was more toxic against HPF. In vivo experiments with amide 8 showed in vivo efficacy on a mouse candidemia model with a larger LD50/ED50 ratio in comparison to amphotericin B.

Polyfunctional compounds containing the 4,6-dialkoxy-7-arylthioheptene moiety as synthetically useful intermediates. The course of lewis acid-induced transformations.

Data on the selectivity of the Lewis acids induced transformations of the title compounds are presented, and the routes leading to formation of products containing either cyclohexane or 1,3-diene units are described.