Halogens, particularly fluorine, chlorine, and bromine, play a pivotal role in modern drug discovery and development. Their incorporation into drug molecules significantly influences physicochemical properties, including lipophilicity, metabolic stability, and target binding affinity. Fluorine, the most commonly used halogen, enhances bioavailability and receptor interactions, as seen in several blockbuster drugs. Chlorine and bromine contribute to hydrophobic interactions and modulate pharmacokinetics, while iodine is less frequently utilized due to its larger atomic size and reactivity. The strategic placement of halogens in drug scaffolds has led to the success of numerous FDA-approved pharmaceuticals across therapeutic areas, including oncology, infectious diseases, and central nervous system disorders. This review explores the structure–activity relationships (SAR) of halogen-containing drugs, highlighting recent approvals (2025), their synthesis (with yields, when available), therapeutic use, and, when experimentally available, the interaction with their biological target macromolecules.

Kv7 voltage‐gated potassium channels play a critical role in controlling electrical properties of excitable tissues. Neuronally‐expressed Kv7 channels are involved in both common and rare neuropsychiatric disorders, ranging from epilepsy to depression and neurodegenerative diseases; thus, they represent attractive therapeutic targets. However, no Kv7 modulator is currently available for clinical use. Improved knowledge of the functional and structural determinants responsible for ligand‐induced Kv7 channel modulation is likely to fill this gap. In the present work, we describe the cryo‐electron microscopy structures of human Kv7.2 channels in complex with two retigabine analogues: compound 60 ( c60 ), which we previously described as a Kv7 activator with improved pharmacokinetic and pharmacodynamic properties, and the newly designed compound 106 ( c106 ), which acts as a potent Kv7 blocker. Although both compounds occupy the same pocket at the S5–S6 interface in the pore domain, docking and molecular dynamics simulations and electrophysiological experiments revealed that the opposite functional behavior is due to their differential interaction, involving the L307 residue. Thus, we herein provide novel mechanistic insights into the molecular mechanisms governing Kv7 channel modulation by exogenous ligands which may prove useful to target Kv7 channels with more potent and selective modulators.

Kv7 voltage‐gated potassium channels play a critical role in controlling electrical properties of excitable tissues. Neuronally‐expressed Kv7 channels are involved in both common and rare neuropsychiatric disorders, ranging from epilepsy to depression and neurodegenerative diseases; thus, they represent attractive therapeutic targets. However, no Kv7 modulator is currently available for clinical use. Improved knowledge of the functional and structural determinants responsible for ligand‐induced Kv7 channel modulation is likely to fill this gap. In the present work, we describe the cryo‐electron microscopy structures of human Kv7.2 channels in complex with two retigabine analogues: compound 60 ( c60 ), which we previously described as a Kv7 activator with improved pharmacokinetic and pharmacodynamic properties, and the newly designed compound 106 ( c106 ), which acts as a potent Kv7 blocker. Although both compounds occupy the same pocket at the S5–S6 interface in the pore domain, docking and molecular dynamics simulations and electrophysiological experiments revealed that the opposite functional behavior is due to their differential interaction, involving the L307 residue. Thus, we herein provide novel mechanistic insights into the molecular mechanisms governing Kv7 channel modulation by exogenous ligands which may prove useful to target Kv7 channels with more potent and selective modulators.

Catechins are characterized by a basic structure consisting of two benzene rings and a hydropyran heterocyclic ring. In (-)-epicatechin (ECT), the substituents in C2 and C3 of the dihydropyran ring are in cis conformation, whereas in (+)-catechin (CT), they are in trans conformation. Catechins tend to interact with membrane proteins, affecting their activity and/or function and metabolic processes. In this study, the impact of CT and ECT on erythrocyte membrane and cell functions was analyzed. Surprisingly, although the two compounds have a very similar structure that differs only in the orientation of the hydroxyl group in C3, they promote different effects on anion exchange through the phospholipid bilayer and on the release of ATP from cells. Anion transport mediated by Band 3 protein is reduced in the presence of CT compared with ECT which conversely increases it, and this observation aligns with the mechanisms of action we hypothesized in silico for the two compounds. Finally, ECT causes an increase in intracellular ATP levels unlike CT, and both molecules cause a decrease in ATP released from the erythrocyte. These findings could pave the way for further studies aimed at better understanding of the potential properties and structure–activity relationships of these molecules.