Hypnotic profile of imines from benzimidazole chalcones: mechanism of synthesis, DFT studies and in silico screening.
A series of 1-(1H-benzimidazol-2-yl)-3-substituted phenylprop-2-en-1-ylidene] amino}-1,3,4-thiadiazole-2- thiols (6a-6f) were synthesized by the acid catalyzed nucleophilic addition reaction between 1-(1H-benzimidazol-2-yl)-3- phenylprop-2-en-1-ones (4a-4f) and 5-amino-1,3,4-thiadiazole-2-thiol. All the synthesized compounds were characterised by IR, (1)HNMR, (13)CNMR, Mass and elemental analyses. A transition state calculation obtained from DFT study to explore the molecular mechanism of action of the synthetic route. The mechanism of synthesis revealed that the imidazole system can make an increase in the electrophilic character of carbonyl carbon in the benzimidazole chalcones. So the electron deficient carbonyl carbon could be efficiently attacked on the amino group of 1,3,4-thiadiazole ring to forms an imine linkage between the two heterocyclic systems. All the titled derivatives at a dose level of 10mg/kg body weight potentiate the hypnotic action of Phenobarbitone (at a dose of 10mg/kg body weight i.p.). The compounds such as 6b, 6a, and 6c showed a significant percentage increase in sleeping time relative to the control experiment 423.8, 387.6 and 329.5 respectively. The preclinical evaluation of the compounds was ascertained by blood-brain barrier, human oral absorption prediction and in silico toxicity assessment.
Bijo
B
Mathew
Jerad
J
Suresh
Sockalingam
S
Anbazhagan
Department of Pharmaceutical Chemistry, Grace College of Pharmacy, Palakkad 678004, Kerala, India. bijovilaventgu@gmail.com.
Vinod
V
Devaraji
D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000378:metabolism; D047188:Chalcones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006993:Hypnotics and Sedatives / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D007097:Imines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D007408:Intestinal Absorption; D051379:Mice; D009125:Muscle Relaxants, Central / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D012890:Sleep / Q000187:drug effects; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D047188:Chalcones; D006993:Hypnotics and Sedatives; D007097:Imines; D009125:Muscle Relaxants, Central