Artefenomel Regioisomer RLA-3107 Is a Promising Lead for the Discovery of Next-Generation Endoperoxide Antimalarials

Abstract

Clinical development of the antimalarial artefenomel was recently halted due to formulation challenges stemming from the drug’s lipophilicity and low aqueous solubility. The symmetry of organic molecules is known to influence crystal packing energies and by extension solubility and dissolution rates. Here we evaluate RLA-3107, a desymmetrized, regioisomeric form of artefenomel in vitro and in vivo , finding that the regioisomer retains potent antiplasmodial activity while offering improved human microsome stability and aqueous solubility as compared to artefenomel. We also report in vivo efficacy data for artefenomel and its regioisomer across 12 different dosing regimens.

Characterization of antimalarial activity of artemisinin-based hybrid drugs

“…The linker stability correlates well with in vivo efficacy in infected mice, as hybrid 1 is more potent than hybrid 2 and ART [29, 32, 34]. While hepatic metabolism and host-mediated degradation could potentially be fine-tuned by chemical modifications and molecular hybridization, as demonstrated here, we recognize that any increase in chemical functionalization and lipophilicity may change other biopharmaceutical parameters [25, 26, 58]. For instance, we observed that our and other designed ART-based hybrids may require a high dosage for effective treatment in mice [32–35].…”

Characterization of antimalarial activity of artemisinin-based hybrid drugs

“…Hybrid 1 is linked via a triazole unit that is not prone to hydrolysis or enzymatic cleavage; however, its tetraethyleneglycol and benzimidazole moieties may undergo metabolism responsible for the degradation of 1 . Although hepatic metabolism and host-mediated degradation could potentially be fine-tuned by chemical modifications and molecular hybridization, as demonstrated here, we recognize that any increase in chemical functionalization and lipophilicity may change other biopharmaceutical parameters ( 25 , 26 , 61 ). For instance, we observed that our and other designed ART-based hybrids may require a high dosage for effective treatment in mice ( 32 – 35 ).…”

“…For drugs derived from 1,2,4-trioxolane or 1,2,4,5-tetraoxane, half-lives can be increased by enhancing the hydrophobicity of the molecule in order to improve the drug-like properties, such as logD, solubility, and metabolic stability, thereby optimizing the pharmacokinetic profile ( 25 , 26 ). Another approach to overcome the shortcomings of ARTs is the development of ART-based hybrid compounds containing a second pharmacophore.…”

Using a Drug Repurposing Strategy to Virtually Screen Potential HIV-1 Entry Inhibitors That Block the NHR Domain of the Viral Envelope Protein gp41

“…В частности, соединение I  МК 0893  является мощным и селективным антагонистом рецепторов глюкагона и использовалось в исследованиях по лечению сахарного диабета 2 типа [46], а соединение II  Авакопан -является одобренным FDA лекарственным препаратом и представляет собой пероральный биодоступный антагонист рецептора комплемента 5а (C5aR) для лечения тяжелого васкулита, связанного с антинейтрофильными цитоплазматическими (ауто)антителами [47,48]. Остальные соединения имеют на сегодняшний день статус кандидатов в лекарственные средства и проходят доклинические (соединение III) [49] и клинические (соединения IVVI) [50][51][52] испытания. Поскольку терапевтический потенциал найденных соединений известен или исследуется в настоящее время, они могут быть использованы в качестве базовых соединений для разработки в ближайшем будущем новых, эффективных и безопасных противовирусных средств, способных связываться с доменм NHR белка gp41 оболочки ВИЧ-1 и блокировать его проникновение в клетку хозяина.…”