Design, synthesis and computational evaluation of a novel intermediate salt of N-cyclohexyl-N-(cyclohexylcarbamoyl)-4-(trifluoromethyl) benzamide as potential potassium channel blocker in epileptic paroxysmal seizures.
The narrow therapeutic range and limited pharmacokinetics of available Antiepileptic drugs (AEDs) have raised serious concerns in the proper management of epilepsy. To overcome this, the present study attempts to identify a candidate molecule targeting voltage gated potassium channels anticipated to have superior pharmacological than existing potassium channel blockers. The compound was synthesized by reacting (S)-(+)-2,3-dihydro-1H-pyrrolo[2,1-c][1,4] benzodiazepine5,11(10H,11aH)-dione with 4-(Trifluoromethyl) benzoic acid (C8H5F3O2) in DMF and N,N'-dicyclohexylcarbodiimide (DCC) which lead to the formation of an intermediate salt of N-cyclohexyl-N-(cyclohexylcarbamoyl)-4-(trifluoromethyl)benzamide with a perfect crystalline structure. The structure of the compound was characterized by FTIR,1H NMR and13C NMR analysis. The crystal structure is confirmed by single crystal X-ray diffraction analysis. The Structure-Activity Relationship (SAR) studies revealed that substituent of fluoro or trifluoromethyl moiety into the compound had a great effect on the biological activity in comparison to clinically used drugs. Employing computational approaches the compound was further tested for its affinity against potassium protein structure by molecular docking in addition, bioactivity and ADMET properties were predicted through computer aided programs.
PG & Research Department of Physics, National College (Affiliated to Bharathidasan University), Tiruchirapalli, 620 001 Tamil Nadu, India.
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Natchimuthu
Bioinformatics Research Laboratory, Eminent Biosciences, Vijaynagar, Indore 452010 Madhya Pradesh, India.
Srinivas
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Bandaru
Bioinformatics Research Laboratory, Eminent Biosciences, Vijaynagar, Indore 452010 Madhya Pradesh, India.
Anuraj
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Nayarisseri
PG & Research Department of Physics, National College (Affiliated to Bharathidasan University), Tiruchirapalli, 620 001 Tamil Nadu, India. Electronic address: suga_ravi@yahoo.co.in.
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Ravi
D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D001812:Blood-Brain Barrier; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D018360:Crystallography, X-Ray; D015195:Drug Design; D004827:Epilepsy / Q000188:drug therapy*; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D026902:Potassium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D066244:Proton Magnetic Resonance Spectroscopy; D013055:Spectrophotometry, Infrared
D001549:Benzamides; D026902:Potassium Channel Blockers; C036152:4-(trifluoromethyl)benzamide
ADMET property prediction; Fluorinated N,N′-dicyclohexylcarbodiimide; K(+) blocker; Molecular docking; Paroxysmal seizures; X-ray structures