Emodepside

This study focuses on the systematic exploration of the emodepside conformations bound to monovalent K+ ion using quantum mechanical density functional theory (DFT) calculations at the M06‐2X/6‐31+G(d,p) level of theory. Nine conformers of emodepside and their complexes with K+ ion were characterized as stationary points on the potential energy surface. The conformational isomers were examined for their 3D structures, bonding, energetics, and interactions with the cation. A cavitand‐like structure (CC) is identified to be the energetically most stable arrangement. To arrive at a better understanding of the K+ ion binding, calculations were initially performed on complexes formed by the K+ and Na+ ions with model ligands (methyl ester and N,N‐dimethyl acetamide). Both the natural bond orbital (NBO) method and the block‐localized wavefunction (BLW) energy decomposition approach was employed to assess the bonding and energetic contributions stabilizing the ion‐bound model complexes. Finally, the solvent effect was evaluated through complete geometry optimizations and energy minimizations for the model ion‐ligand complexes and the emodepside‐K+ bound complexes using an implicit solvent model mimicking water and DMSO.

AWZ1066S has been developed as a potential treatment for the neglected tropical diseases lymphatic filariasis and onchocerciasis. AWZ1066S targets the Wolbachia bacterial endosymbiont present in the causative nematode parasites. This phase 1, first‐in‐human study aimed to assess the safety and pharmacokinetics of AWZ1066S in healthy human participants. In a randomized double‐blind, placebo‐controlled, single ascending dose study, healthy adults received a single oral dose of AWZ1066S (or placebo) and were followed up for 10 days. The planned single doses of AWZ1066S ranged from 100 to 1600 mg, and each dose was administered to a cohort of 8 participants (6 AWZ1066S and 2 placebo). In total 30 people participated, 18 (60%) female, median age 30.0 years (minimum 20, maximum 61). The cohorts administered 100, 200, 300, and 400 mg of AWZ1066S progressed unremarkably. After single 700‐mg doses all 4 participants developed symptoms of acute gastritis and transient increases in liver enzymes. The severity of these adverse events ranged from mild to severe, with 1 participant needing hospital admission. Pharmacokinetic analysis indicated that AWZ1066S is rapidly absorbed with predictable pharmacokinetics. In conclusion, safety concerns prevented this study from reaching the human exposures needed for AWZ1066S to be clinically effective against lymphatic filariasis and onchocerciasis.