Outward current conducted by human ether-à-go-go-related gene type 1 (hERG1) K+ channels is important for action potential repolarization in the human ventricle. Rapid, voltage-dependent inactivation greatly reduces outward currents conducted by hERG1 channels and involves conformational changes in the ion selectivity filter (SF). Recently, compounds have been found that activate hERG1 channel function by modulating gating mechanisms such as reducing inactivation. Such activating compounds could represent a novel approach to prevent arrhythmias associated with prolonged ventricular repolarization associated with inherited or acquired long QT syndrome. ICA-105574 (ICA), a 3-nitro-n-(4-phenoxyphenyl) benzamide derivative activates hERG1 by strongly attenuating pore-type inactivation. We previously mapped the putative binding site for ICA to a hydrophobic pocket located between two adjacent subunits. Here, we used the recently reported cryoelectron microscopy structures of hERG1 to elucidate the structural mechanisms by which ICA influences the stability of the SF. By combining molecular dynamics simulations, voltage-clamp electrophysiology, and the synthesis of novel ICA derivatives, we provide atomistic insights into SF dynamics and propose a structural link between the SF and S6 segments. Further, our study highlights the importance of the nitro moiety, at the meta position of the benzamide ring, for the activity of ICA and reveals that the (bio)­isosteric substitution of this side chain can switch the activity to weak inhibitors. Our findings indicate that ICA increases the stability of the SF to attenuate channel inactivation, and this action requires a fine-tuned compound geometry.

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A mechanistic investigation of the acid-catalysed redox-neutral arylation of ynamides intertwining ESI-MS, DFT and experiments reveals diverse pathways available from an otherwise simple-looking transformation.

The left‐hand fragment 2 of the novel antibiotic kendomycin (1) has been synthesized by an aldol addition and a Michael‐type 1,4‐addition of a C5 alcohol with a C9–C11 enone. Compound 2 shows an interesting atropisomerism around the C4a‐C5‐sp2‐sp3 bond. The atropisomers can be separated in pure forms by low‐temperature high‐pressure liquid chromatography.