Design and bio-evaluation of indole derivatives as potent Kv1.5 inhibitors
Graphical abstract
Introduction
As the most common sustained form of arrhythmia, atrial fibrillation (AF) affects a large and growing population,1, 2, 3, 4 some further projections5 indicate that the morbidity of AF will at least double in the next 5 decades with the ageing population and will lead to substantial mortality of stroke and heart failure.6, 7
Antiarrhythmic medications remain a mainstay in the treatment of AF.8 Currently the antiarrhythmic agents,9 such as dofetilide and sotalol, are limited in efficacy and considerable risks2, 10 for their unselective blockade of the potassium currents in both atrial and ventricular myocytes.11 One interesting potential target is the ultra-rapid potassium channel (IKur, encoded by Kv1.5 gene) which is functionally expressed in the atrium but not ventricle in humans,12, 13, 14 suggesting Kv1.5 potassium channel as a novel selective target for the treatment of AF.15
Our previous studies16, 17 reported a pharmacophore model of Kv1.5 (Fig. 1) that was made up of one hydrogen bond acceptor, one aromatic ring, and two hydrophobic groups. After structure-based virtual screening of the compounds from the Maybridge database, in silico druglike property prediction and electrophysiological evaluation were undertaken,18, 19 leading to a lead compound RH01617 with outstanding Kv1.5 inhibitory activity (Fig. 1). Herein, with the aim of carefully investigating the structure–activity relationship (SAR), three series of derivatives containing 30 compounds were designed, synthesized and bioevaluated. Among them, compounds IIIi and IIIl showed potent activity and were chosen for further pharmacodynamic evaluations. The results showed that compound IIIl possessed remarkable selectivity Kv1.5 potassium channel activity over hERG (human ether-a-go-go gene) potassium channel and sodium channel, while the atrial selective profile was also proved in the animal model in vitro.
Section snippets
Chemistry
Compounds Ia–Ii were prepared from methyl tryptophan ester hydrochloride and commercially available or synthesized sulfonyl chloride derivatives (Scheme 1). Starting from 4-hydroxybenzenesulfonate and alkyl bromide, compounds 2a–2e were obtained via substitution and acylation reaction. Compounds 3a–3b were obtained from tryptophan or phenylalanine and CH3OH in the presence of SOCl2. Reaction of 2a–2e with 3a–3b in CH2Cl2 provided the target compounds Ia–Ii. Compound Ia was hydrolyzed by LiOH (1
Conclusion
Drug targeted cardiac Kv1.5 channel is supposed to have a safety advantage over current market drugs. In this study, we have designed and synthesized 29 novel compounds modified from the lead compound Ia which was identified from virtual screening we previously reported, aiming at discovering potent and selective Kv1.5 inhibitors. Structural modifications mainly addressing the side chain of phenyl, ester group, coupling chain and N-substituents at indolyl enabled modulation of Kv1.5 inhibitory
General methods, materials, and spectroscopic details
Melting points were measured with a Melt-Temp II instruments. IR spectra were recorded on a Nicolet Impact 410 spectrometer. EI-MS was recorded Shimadzu GC–MS 2050 apparatus; ESI-MS was recorded on Agilent 1100 LC/MSD (70 ev) spectrometers. 1H NMR and 13C NMR spectra were recorded on Bruker AV-300 or AV-500 MHz instruments in DMSO-d6 and CDCl3 using tetramethylsilane (TMS) as the internal standard. Chemical shifts were reported as d values (parts per million) relative to solvent peak. Coupling
Acknowledgments
The authors thank Dr. Gui-Rong Li (Department of Medicine and Department of Physiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, SAR, China) for providing the HEK293 cells in which Kv1.5 channels are stably expressed.
This work was supported by the Project Program of State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, the innovation Program for the Postgraduates in Jiangsu in 2012, National Major Science
References and notes (41)
- et al.
Lancet
(2010) - et al.
Lancet
(2007) - et al.
J. Mol. Graphics Modell.
(2008) - et al.
Biochem. Biophys. Res. Commun.
(2008) - et al.
Bioorg. Med. Chem. Lett.
(2008) - et al.
Bioorg. Med. Chem. Lett.
(2009) - et al.
Bioorg. Med. Chem. Lett.
(2009) - et al.
Bioorg. Med. Chem. Lett.
(2010) - et al.
Tetrahedron
(1998) - et al.
Bioorg. Med. Chem.
(2007)
Bioorg. Med. Chem.
Int. J. Cardiol.
Nat. Rev. Drug Disc.
Europace
Expert Opin. Pharmacother.
QSAR Comb. Sci.
Circulation
Cleve. Clin. J. Med.
Europace
Expert Opin. Drug Saf.
Cited by (23)
Quinazolinone dimers as a potential new class of safer Kv1 inhibitors: Overcoming hERG, sodium and calcium channel affinities
2021, Bioorganic ChemistryCitation Excerpt :There are three characteristics of class I antiarrhythmics: an aliphatic amine, a hydrophobic moiety and a linker containing a hydrogen-bond acceptor, usually a carbonyl group [50]. Also, increasing the overall bulkiness of the molecules decreases their affinity to Nav channels [51]. A quinazolinone dimer with an ethylene linker (3a-i) seems to be an all-in-one scaffold, as I) it has a double ethylbenzamide core; II) it incorporates a nitrogen-containing heterocyclic (quinazolinone) moiety; III) it keeps the required pharmacophoric features; IV) it is bulky enough to avoid getting into the deep inner pore of Kv1.x channels.
Tris(pentafluorophenyl)borane-Catalyzed Formal Cyanoalkylation of Indoles with Cyanohydrins
2021, Journal of Organic ChemistrySynthesis of N-2(5H)-furanonyl sulfonyl hydrazone derivatives and their biological evaluation in vitro and in vivo activity against MCF-7 breast cancer cells
2021, Bioorganic ChemistryCitation Excerpt :As a quantitative measure of DNA damage, tail intensity (percentage DNA in the tail) was analyzed by Comet Assay Software Pect (CaspLab) software. Immunofluorescence staining and confocal microscopy were performed as described previously [45]. MCF-7 cells were grown in culture medium and treated with 5 k of 0, 10, 20, and 40 μM for 24, 48, and 72 h, respectively.
Synthesis of structurally diverse biflavonoids
2018, TetrahedronCitation Excerpt :Isoflavone-chalcone biflavonoid 9 was targeted in order to explore the potential to generate biflavonoids with heteroaromatic moieties such as indoles which are known to be associated with interesting biological properties [23]. Preparation of the required indole bromochalcone 31 commenced with Vilsmeier-Haack formylation of indole 28 to give aldehyde 29 [24]. ( Scheme 4).
- 1
These authors contributed equally to this work.