title: Design and synthesis of some new theophylline derivatives with bronchodilator and antibacterial activities.
abstract: Methylxanthines especially theophylline have been recognized as potent bronchodilators for the relief of acute asthma for over 65 years. Recently, it was found that bacterial infection plays a role in asthma pathogenesis. Accordingly, the present work involves the synthesis of 6-(4-(un)substituted phenyl)thiazolo[2,3-f]theophyllines 2a-g and different series of 8-(1,2,4-triazol-3-ylmethylthio)theophyllines 6-9. The chemical structures of the target compounds were proved by IR, (1)H NMR, (13)C NMR, EI-MS and HRMS spectroscopic techniques along with elemental analyses. The bronchodilator activity of fifteen compounds was determined in vivo by acetylcholine induced bronchospasm in anaesthetized guinea pigs. Results revealed that all compounds showed moderate to good activity; in addition, five compounds exhibited a bronchodilator activity nearly similar to that of aminophylline as a standard. The antibacterial activity of all the target compounds was investigated in vitro against both Gram-positive and Gram-negative bacterial strains. Results revealed that some compounds showed more potent antibacterial activity than ampicillin as a standard. Acute toxicity study for four target compounds revealed that none of these derivatives showed significant toxicity up to 300 mg/kg. It was found that compound 8c combined both promising bronchodilator and antibacterial activities. This compound could be subjected for further investigations as a new possible candidate in the treatment of bronchial asthma.
authors.affiliation: Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Egypt. alaa_hayalah@yahoo.com
authors.forename: Alaa M
authors.initials: AM
authors.lastname: Hayallah
authors.forename: Walid A
authors.initials: WA
authors.lastname: Elgaher
authors.forename: Ola I
authors.initials: OI
authors.lastname: Salem
authors.forename: Abdel Alim M Abdel
authors.initials: AA
authors.lastname: Alim
mesh_terms: D000628:Aminophylline / Q000494:pharmacology; D000667:Ampicillin / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy / Q000382:microbiology / Q000503:physiopathology; D001986:Bronchial Spasm / Q000188:drug therapy; D001993:Bronchodilator Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D013806:Theophylline / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D023382:Toxicity Tests, Acute
chemical_list: D000900:Anti-Bacterial Agents; D001993:Bronchodilator Agents; D000628:Aminophylline; D000667:Ampicillin; D013806:Theophylline