Full Paper Synthesis and Biological Activity of Functionalized Indole-2- carboxylates, Triazino- and Pyridazino-indoles Adel A. El-Gendy 1 , Mohamed M. Said 2 , Nagat Ghareb 2 , Yasser M. Mostafa 3 , and El Sayed H. El-Ashry 4 1 Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt 2 Organic Chemistry Department, Faculty of Pharmacy, Suez-Canal University, Ismailia, Egypt 3 Pharmacology Department, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt 4 International Center for Chemical and Biological Sciences (HEJ Research Institute for Chemistry), Karachi University, Karachi, Pakistan Condensation of aryl hydrazines with ethyl pyruvate gave the respective hydrazones 4 – 6; Fischer indolization led to substituted-1H-indole-2-carboxylic acid ethyl esters 7 – 9. The Mannich reaction of these compounds with formaldehyde and morpholine yielded ethyl 3-(morpholino- methyl)-substituted-1H-indole-2-carboxylates 10-12. The 5,7-dichloro- 1H-indole-2-carbohydrazide 13 was cyclized with methyl orthoformate in DMF to give 6,8-dichloro[1,2,4]triazino[4,5-a]indol- 1(2H)-one 14. Vilsmeier – Haack formylation of 7–9 gave ethyl 3-formyl-substituted-1H-indole-2- carboxylates 15–17 whose 2,29-((5-chloro-2-(ethoxycarbonyl)-1H-indol-3-yl)methylene)bis-(sulfane- diyl) diacetic acid 18 was prepared. The reaction of 15 and 16 with substituted anilines by con- ventional and microwave methods gave ethyl 3-(N- aryliminomethyl)-5-halo-1H-indole-2-carboxy- lates 19 – 29. In a cyclocondensation reaction of 19 – 25 with thiolactic acid or thioglycolic acid substituted indolylthiazolidinones 30 – 33 were prepared. Reaction of hydrazine hydrate with 15 – 17 did not give the respective hydrazones but directly led to the cyclized products substi- tuted-3H-pyridazino[4,5-b]indol-4(5H)-ones 34 – 36, while a reaction with 2,4-dichlorophenylhy- drazine yielded the uncyclized hydrazones. The chlorination of 35 and 36 with POCl 3 gave pyri- dazino[4,5-b]indoles 39 and 40, respectively; reaction of the latter compounds with morpholine gave 4-(substituted-5H-pyridazino[4,5-b]indol-4-yl)morpholine 41 and 42. Mannich reaction of 34 with formaldehyde and N- ethylpiperazine gave 8-chloro-3-((4-ethylpiperazin-1-yl)methyl)-3H-pyri- dazino[4,5-b]indol-4(5H)-one 43. The microwave assistance of selected reactions has a profound effect on the reaction speed. The structures of the new compounds were confirmed by both ana- lytical and spectral data. Some compounds were subjected to investigations concerning their antimicrobial, tranquilizing, and anticonvulsant activities. Keywords: Fischer Indolization / Substituted phenylhydrazone / Schiff's base / Vilsmeier – Haack Formylation / Thiolac- tic acid / Received: July 31, 2007; accepted: November 30, 2007 DOI 10.1002/ardp.200700161 Supporting Information for this article is available from the author or on the WWW under http://www.wiley-vch.de/con- tents/jc_2019/2007_00161_s.pdf Introduction The incorporation of a nitrogen heterocycle on an ali- phatic side chain at position-3 of the indole-2-carboxylate led to diverse biological effects as anti-inflammatory [1], selective D 4 ligands [2], and 5-HT 3 antagonists [3]. Indole compounds containing either linked or fused thiazolidi- none moieties were found to possess antibacterial [4 – 5], fungicidal [6], antifertility [7], and anticonvulsant [8 – 9] activities. Likewise, the pyridazino[4,5-b]indole-ring sys- Correspondence: E. S. H. El Ashry, Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt. E-mail: Eelashry60@hotmail.com Fax: +20 342 71360 i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 294 Arch. Pharm. Chem. Life Sci. 2008, 341, 294 – 300