A systematic analysis of all synthetic and chemoenzymatic methodologies for the preparation of aminoglycosides for a variety of applications (therapeutic and agricultural) reported in the scientific literature up to 2017 is presented. This comprehensive analysis of derivatization/generation of novel aminoglycosides and their conjugates is divided based on the types of modifications used to make the new derivatives. Both the chemical strategies utilized and the biological results observed are covered. Structure-activity relationships based on different synthetic modifications along with their implications for activity and ability to avoid resistance against different microorganisms are also presented.
Since the discovery of the first aminoglycoside (AG), streptomycin, in 1943, these broad-spectrum antibiotics have been extensively used for the treatment of Gram-negative and Gram-positive bacterial infections. The inherent toxicity (ototoxicity and nephrotoxicity) associated with their long-term use as well as the emergence of resistant bacterial strains have limited their usage. Structural modifications of AGs by AG-modifying enzymes, reduced target affinity caused by ribosomal modification, and decrease in their cellular concentration by efflux pumps have resulted in resistance towards AGs. However, the last decade has seen a renewed interest among the scientific community for AGs as exemplified by the recent influx of scientific articles and patents on their therapeutic use. In this review, we use a non-conventional approach to put forth this renaissance on AG development/application by summarizing all patents filed on AGs from 2011–2015 and highlighting some related publications on the most recent work done on AGs to overcome resistance and improving their therapeutic use while reducing ototoxicity and nephrotoxicity. We also present work towards developing amphiphilic AGs for use as fungicides as well as that towards repurposing existing AGs for potential newer applications.
The rise and emergence of resistance to antifungal drugs by diverse pathogenic fungal strains have resulted in an increase in demand for new antifungal agents. Various heterocyclic scaffolds with different mechanism of action against fungi have been investigated in the past. Herein, we report the synthesis and antifungal activities of 18 alkylated mono-, bis-, and trisbenzimidazole derivatives, their toxicities against mammalian cells, as well as their ability to induce reactive oxygen species (ROS) in yeast cells. Many of our bisbenzimidazole compounds exhibited moderate to excellent antifungal activities against all tested fungal strains, with MIC values ranging from 15.6–0.975 µg/mL The fungal activity profiles of our bisbenzimidazoles were found to be dependent on alkyl chain length. Our most potent compounds were found to display equal or superior antifungal activity when compared to the currently used agents amphotericin B, fluconazole, itraconazole, posaconazole, and voriconazole against many of the strains tested.
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