Synthesis and anticonvulsant activity of some new thiazolo[3,2-a][1,3]diazepine, benzo[d]thiazolo[5,2-a][12,6]diazepine and benzo[d]oxazolo[5,2-a][12,6]diazepine analogues

• Published in: European journal of medicinal chemistry Vol. 46; no. 11; pp. 5567 - 5572
• Main Authors: El-Subbagh, Hussein I., Hassan, Ghada S., El-Azab, Adel S., Abdel-Aziz, Alaa A.-M., Kadi, Adnan A., Al-Obaid, Abdulrahman M., Al-Shabanah, Othman A., Sayed-Ahmed, Mohamed M.
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 01.11.2011; Elsevier
• Subjects: Animals; Anticonvulsant activity; Anticonvulsants - chemical synthesis; Anticonvulsants - chemistry; Anticonvulsants - pharmacology; Anticonvulsants - therapeutic use; Anticonvulsants. Antiepileptics. Antiparkinson agents; Azepines - chemical synthesis; Azepines - chemistry; Azepines - pharmacology; Azepines - therapeutic use; Benzo[d] oxazolo[5,2-a][12,6]diazepine; Benzo[d]thiazolo[5,2-a][12,6]diazepine; Biological and medical sciences; Chemistry Techniques, Synthetic; Chemistry, Medicinal; Hydrophobic and Hydrophilic Interactions; Life Sciences & Biomedicine; Male; Medical sciences; Mice; Neuropharmacology; Pentylenetetrazole - adverse effects; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Seizures - chemically induced; Seizures - drug therapy; Structure-Activity Relationship; Synthesis; Thiazolo[3,2-a][1,3]diazepine; Thiazolo[3,2-a][1,3]diazepine; Anticonvulsant activity; Synthesis; Benzo[d] oxazolo[5,2-a][12,6]diazepine; Benzo[d]thiazolo[5,2-a][12,6]diazepine; HYPNOTIC HIE-124; SUBTYPES; PHARMACOLOGY; RECEPTOR; METABOLIC PROFILE; ETHYL; Sulfur nitrogen heterocycle; Intraperitoneal administration; Rodentia; Anticonvulsant; Tricyclic compound; Vertebrata; Mammalia; Structure activity relation; Mouse; Chlorine Organic compounds; Animal; Bicyclic compound; Bromine Organic compounds; Aromatic compound; Chemical synthesis; Oxygen nitrogen heterocycle
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.09.021

A new series of 6,7-dihydro-thiazolo[3,2-a][1,3]diazepines (9–12), benzo[d]thiazolo[5,2-a][12,6]diazepines (19–21) and benzo[d]oxazolo[5,2-a][12,6]diazepine (24) analogues were synthesized and evaluated for their anticonvulsant activity. Compounds (E)-2-bromo-6,7-dihydro-thiazolo[3,2-a][1,3]diazepine-8(5H)-thione (12), 3-chloro-benzo[d]thiazolo[5,2-a][12,6]diazepin-10-one (20), and 4-chloro-benzo[d]oxazolo[5,2-a][12,6] diazepin-10-one (24) showed 100% protection against PTZ- and bicuculline-induced seizures; 70%, 33%, 70% protection against MES-induced tonic extension; and 70%, 66%, 100% protection against picrotoxin-induced convulsions, respectively. Compounds 12, 20, and 24 proved to act as GABAA receptor agonists, with ED50 values of 252, 380, 251 mg/kg; TD50 values of 398, 417, 355 mg/kg; PI values of 1.58, 1.09, 1.41; LD50 values of 380, 617, 537 mg/kg and TI values of 1.51, 1.62, 2.14, respectively. Compounds 12, 20 and 24 showed 100% protection against PTZ- and bicuculline-induced seizures; 70%, 33%, 70% protection against MES-induced tonic extension; and 70% 66% 100% protection against picrotoxin-induced convulsions, respectively. [Display omitted] ▸ Thiazolo-diazepine, benzothiazolo-diazepine and benzooxazolo-diazepine analogues were synthesized. ▸ Anticonvulsant activity of the new compounds was evaluated. ▸ Compounds 12, 20, and 24 showed 100% protection against PTZ-induced seizures. ▸ Compounds 12, 20, and 24 proved to act as GABAA receptor agonist.