Exploring Chemical Substructures Essential for hERG K⁺ Channel Blockade by Synthesis and Biological Evaluation of Dofetilide Analogues

Abstract

In this study we followed a new approach to analyze molecular substructures required for hERG channel blockade. We designed and synthesized 40 analogues of dofetilide (1), a potent hERG potassium channel blocker, and established structure-activity relationships (SAR) for their interaction with this important cardiotoxicity-related off-target. Structural modifications to dofetilide were made by diversifying the substituents on the phenyl rings and the protonated nitrogen and by varying the carbon chain length. The analogues were evaluated in a radioligand binding assay and SAR data were derived with the aim to specify structural features that give rise to hERG toxicity.

An Efficient K2CO3-Promoted Synthesis of 1-Bromo-2-aryloxyethane Derivatives and Evaluation of Larval Mortality against Aedes aegypti

“…Without the presence of anhydrous K 2 CO 3 , no reaction was observed. First, the influence of the reaction temperature (20,40,60, and 80 ∘ C) on 1-bromo-2-phenoxyethane synthesis was tested (Table 1(a)). The tested experimental reaction conditions were phenol (10 mmol), 1,2-dibromoethane (50 mmol), anhydrous K 2 CO 3 (30 mmol), 6 h of reaction time in acetonitrile (50 mL).…”

“…Particularly, 1-bromo-2-aryloxyethane derivatives have been prepared from phenols and 1,2-dibromoethane, employing different bases and solvents, and include Na 2 CO 3 /glycerol, [19], and NaH/EtOH [20], among other modifications to the classical Williamson ether synthesis. The use of synthetic organic compounds as alternative sources of insecticidal/larvicidal agents in the fight against the dengue, Zika, and chikungunya vector-borne diseases has become inevitable.…”

Assessing hERG Pore Models As Templates for Drug Docking Using Published Experimental Constraints: The Inactivated State in the Context of Drug Block

“…52 However, in low energy score docking poses, no hydrogen bond interactions were made with the side chain OH of T623 for any drug, and few hydrogen bonds with the S624 side chain hydroxyl were found in Flexidock poses. For dofetilide and E-4031, enhanced binding affinity is obtained with some analogues in which aromatic ring substituents are removed or replaced with a methyl group, 31,32 demonstrating that interactions of ring substituents with T623 and/or S624 side chains are not critical for high affinity block of hERG by these drugs. Imai et al suggested that hydrogen bond interactions between the Y652 phenolic OH and T623 side chain hydroxyl might stabilize Y652 side chain rotamers optimized for drug binding, 24 and similar interactions involving the side chain OH of S624 (e.g., Figure 7B) might also play such a role.…”

“…20,21 We make use of several recent key experimental observations that inform on the essential structural elements of hERG blockers and the likely interactions of these molecules with aromatic residues within the hERG pore. 24,31−33 This analysis gives insight into the nature of the inactivated state of hERG in the context of drug binding.…”

Copper‐Catalyzed Intermolecular Hydroamination of Arylamines or Aza‐Heterocycles with Nitrostyrene Derivatives

“…This compound has been previously reported and spectra data match described [18]. The crude product was purified using silica gel column chromatography (EtOAc:hexanes = 1:3).…”