ABSTRACT K V 7.1 antagonists hold potential for the treatment of diarrhea, reflux esophagitis, and hypoinsulinemia. The 1,4‐benzodiazepine L768,673 (( R )‐ 1 ) is a potent and selective K V 7.1 channel blocker with a higher apparent affinity for the K V 7.1 ion channel than other K V 7.1 modulators including (R)‐L3. In this study, L768,673 (( R )‐ 1 ) was systematically modified at two positions, and the inhibitory effects of the resulting 1,4‐benzodiazepines were evaluated by two‐electrode voltage‐clamp (TEVC) experiments. Acylation of the primary amines rac ‐ 7 and 9 provided amides 8 and 10a – e . Alkylation of secondary lactam 10a led to tertiary lactams 12a – c . Secondary lactams 10a – e and tertiary lactams 12a , b with large 1‐substituents could not inhibit the K V 7.1 channel. However, racemic 3‐fluoropropyl derivative 12c was as active as the enantiomerically pure lead compound ( R )‐ 1 rendering 12c an interesting starting point for the development of an 18‐fluorine labeled PET tracer.
ABSTRACT The high structural similarity among the catalytically active human carbonic anhydrase (CA) isozymes makes the identification of high‐affinity, isozyme‐selective ligands particularly challenging. This study investigates benzenesulfonamide–imidazole hybrids as inhibitors of CAs and explores structural features of their interactions. Binding affinity was quantified by thermal shift assay, while isothermal titration calorimetry and enzymatic inhibition assays were used to further characterize ligand–CA interactions. Most of the synthesized imidazole‐bearing compounds showed high nanomolar affinity for CAII, CAVII, and CAIX isozymes, and their interactions were enthalpically favorable. Crystal structures of CA isozyme–ligand complexes indicate that hydrophobic interactions are the dominant factor in the binding of the examined benzenesulfonamide ligands ( 4a , 4b , 8 , and 12 ) with CAI, CAII, CAXII, and CAXIII. Combined studies of protein–ligand binding and inhibition, and X‐ray crystallography enable analysis of the structural factors responsible for high affinity, which is essential for developing more potent and selective inhibitors for a particular CA isozyme.
ABSTRACT As part of our ongoing research in heterocyclic chemistry, we report herein the synthesis of novel pentaheterocyclic systems that integrate pyrrolo[1,2‐ a ]pyrimidine, pyrido[1,2‐ a ]pyrimidine, or pyrimido[1,2‐ a ]azepine fragments with a 2,7‐naphthyridine moiety within a single molecular framework. These compounds represent promising scaffolds for drug discovery. The synthetic approach commenced from the corresponding amines and ethyl acrylate and involved a sequence of nucleophilic substitution and cyclization reactions. The structures of the synthesized compounds were elucidated using spectroscopic techniques and unambiguously confirmed by single‐crystal X‐ray diffraction analysis. Biological evaluation revealed that the newly synthesized 2,7‐naphthyridine‐based systems exhibit neuroprotective activity. Although they displayed only weak anticonvulsant effects in the pentylenetetrazole‐induced seizure model, they demonstrated notable anxiolytic and antidepressant properties, highlighting their potential as lead compounds for the development of novel neuroactive agents. Furthermore, molecular docking studies were performed, and the results were found to be consistent with the experimental findings.
ABSTRACT A series of new benzo[ b ][1,8]naphthyridine derivatives ( 3a–g ) was synthesized and biologically evaluated as multifunctional antioxidant and cholinesterase inhibitory agents. The target compounds were prepared through a multi‐step strategy involving amination followed by Friedländer‐type condensation with activated methylene compounds. In vitro evaluation using the Ellman method revealed notable inhibitory activity against acetylcholinesterase (AChE, IC 50 = 2.29–9.51 µM) and butyrylcholinesterase (BChE, IC 50 = 11.37–67.21 µM). Compound 3e emerged as the most active dual inhibitor of AChE (IC 50 = 2.29 µM) and BChE (IC 50 = 11.37 µM), whereas compounds 3b , 3c , and 3g were inactive toward BChE, highlighting strong AChE selectivity with selectivity indices up to 8.04. The antioxidant activity of the derivatives was assessed using β‐carotene–linoleic acid, CUPRAC, and superoxide DMSO alkaline assays. Several compounds exhibited significant antioxidant potential, with compound 3d showing the strongest lipid peroxidation inhibition (IC 50 = 0.13 ± 0.02 mM). whereas compounds 3a (0.33 ± 0.01 mM) and 3b (0.063 ± 0.025 mM) displayed superoxide scavenging activity comparable to α‐tocopherol. Structure–activity relationship analysis indicated that electron‐donating substituents enhanced radical stabilization and reducing power. Density functional theory (DFT) calculations at the B3LYP/6‐311 G(d,p) level revealed that electron‐withdrawing substituents reduced HOMO–LUMO gaps and increased electrophilicity and charge‐transfer ability. Overall, the combined biological, docking, and theoretical results findings highlight the naphthyridine scaffold as a promising platform for the development of multifunctional agents targeting neurodegenerative disorders.
ABSTRACT The aim of this study was to characterize the pharmacological profile of a newly synthesized compound 5 ( R,S) −1‐(5‐{4‐[(1,1'‐biphenyl)‐2‐yl]piperazin‐1‐yl}pentyl)−3',4'‐dihydro‐2' H ‐spiro[imidazolidine‐4,1'‐naphthalene]‐2,5‐dione, designed as a dual‐acting ligand targeting the serotonin 5‐HT 7 receptor and voltage‐gated sodium channels. In vitro studies demonstrated that compound 5 exhibits high affinity for the 5‐HT 7 receptor (K i = 19 nM), comparable to the reference ligand LP‐211, and potent inhibition of sodium channels, markedly stronger than that of phenytoin. Functional assays confirmed that compound 5 acts as a 5‐HT 7 receptor antagonist (K b = 87 nM) with no detectable agonist activity. In addition, the compound showed negligible affinity for the serotonin transporter (SERT), indicating a favorable selectivity profile. Molecular docking studies revealed a stable binding mode of compound 5 within the orthosteric site of the 5‐HT 7 receptor, consistent with known GPCR interaction patterns. Modifications to compound 5 improved its safety by reducing hepatocytotoxicity in HepG2 cells. In vivo behavioral experiments demonstrated significant antidepressant‐like effects in the forced swim test and anxiolytic‐like effects in the four‐plate test in mice.
