A novel class of fast‐acting antimalarial agents: Substituted 15‐membered azalides

Abstract

Analyzed and interpreted data, Wrote the paper; Mirjana Bukvic: Wrote the paper; Vesna Erakovic Haber: Analyzed and interpreted data, Wrote the paper; Radan Spaventi: Designed research and interpreted data. All authors are accountable for accuracy and integrity of the presented results and have given their approval of the version to be published. Conflict of interest statement FJG, SFB, MSM and AK are employees of GSK, and other authors declare that they have no conflict of interest and no commercial associations that might pose a conflict of interest in connection with the submitted article.

Targeting malaria parasites with novel derivatives of azithromycin

“…Azithromycin and analogues previously found to have quick killing activity ( Burns et al., 2020 ) have regularly been reported to have cytotoxicity levels in vitro (CC 50 ) of >10 μM, and often show no toxicity to mammalian cells at >50 μM ( Bukvic Krajacic et al., 2011 ; Peric et al., 2012 ; Peric et al., 2021 ). Therefore, we next investigated the potential of mammalian cell cytotoxicity for a focused group of analogues on the human hepatocellular carcinoma, Huh-7D, cell line ( McKim, 2010 ).…”

“…These data suggest that one of the sites of azithromycin analogues quick-killing activity could be the parasite’s food vacuole. Indeed, azithromycin is known to accumulate within acidic compartments of various cells ( Kanoh and Rubin, 2010 ; Stepanic et al., 2011 ) and the cationic profile and lipophilic properties of azithromycin are improved through modification ( Wilson et al., 2015 ; Peric et al., 2021 ) which may potentiate the accumulation and damage caused by the drug within acidic compartments. Further supporting this possibility, compound C1 also caused a build-up of peptides that could be linked back to haemoglobin, a signature not shared with azithromycin, dihydroartemisinin or chloroquine in these experiments that highlights that activity against the food vacuole may be an important mechanism for azithromycin analogues, in addition to other multi-factorial actions.…”

The dark side of drug repurposing. From clinical trial challenges to antimicrobial resistance: analysis based on three major fields

“…Furthermore, an additional study determined that the supplementation of azithromycin to seasonal malaria chemoprevention did not yield improved nutritional outcomes among children ( 114 ). Furthermore, novel derivatives of azithromycin that exhibit swift action have been developed, manifesting exceptional antimalarial activity in both in vitro and in vivo settings, while employing a distinct mode of action compared to the more gradual acting azithromycin ( 115 ). Although azithromycin has indeed exhibited potential as an antimalarial agent, further investigation is necessary to optimize its efficacy and comprehend its mechanisms of action.…”

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

“…The discovery of new biologically active substances represents not only an advance in the chemistry field but also offers innovative chances for pharmacological and biomedical sciences. Every year, several molecules are discovered and studied against different types of diseases, such as cancer [1,2], malaria [3,4], Chagas disease [5,6], HIV [7,8], depression [9,10], amnesia [11], Alzheimer [12], and maybe even in a more recent scenario, COVID-19 [13]. Even though many compounds are found to present activity against these diseases, only a few of them become approved, due to their toxicity or other issues Scheme 1: Schematic overview of transition metals studied in C-H activation processes.…”