SYNTHESIS AND ANTIVIRAL ACTIVITY OF NEW 4- (PHENYLAMINO)THIENO [2,3-Ä]P YRIDINE DERIVATIVES Alice M. R. Bernardino 3 *; Luiz C. S. Pinheiro 3 , Vitor Francisco Ferreira 3 ; Alexandre R. Azevedo 3 ; Jose W.zyxwvutsrqponmlkjihgfedcbaVUTSRQPONMJIHGFEDCBA dezutronlihgebaTSPMLIFC Μ. Carneiro b ; Thiago M. L. Souza 0vutsrponmliedcaUQIFD and Izabel C. P. P. Frugulhetti 0 "Universidade Federal Fluminense, Instituto de Quimica, Departamento de Quimica Orgänica, Programa de Pös-Graduafäo em Quimica Orgänica, Campus do Valonguinho, CEP 24210-150, Niteröi - RJ, Brasil Universidade Federal Fluminense, Instituto de Quimica, Departamento de Quimica Inorgänica 'Universidade Federal Fluminense, Departamento de Biologia Celular e Molecular, Instituto de Biologia yxvutsrponmlihgedcbaTPM * Corresponding author: E-mail address: alice@rmn.uff.br Abstract: Several new 4-(phenylamino)thieno[2,3-f>]pyridines (6a-e) were synthesized and tested against herpes simplex virus type 1 (HSV-1). For the first time one compound (6a) of this heterocyclic system showed 86% of inhibitory indicating that these compounds retain antiviral potency in comparison to the parent pirazolo-pyridine derivatives. 5 The compounds thieno[2,3-i]pyridine (6) are structurally promising since it contains at least two motifs that could be easily modified: the thienopyridine and phenyl portions. Recently, a novel classes of thienopyrimidines and thienopyridines have been identified as potent inhibitors of VEGFR-2 kinase, which is the key component of the signaling pathway responsible for the sprouting and maturation of new blood vessels from tumors. 1 Also, a new series of thienopyrimidines were synthesized and studied as inhibitors of dihydrofolate reductase from Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium} The synthesis of thieno[2,3-6]pyridine was first reported in 1913 and represents only one of six possible isomers. 3 Their chemistry has been the subject of two reviews. 4 R - H.rp p- CH 3 , p- OCHj, <r OCH 3 , p- NOj R,- CH 3 , Ph Rj- CO2B. CO,H Since it was found that 4-anilino-l//-pyrazolo[3,4-£>]pyridine (7) derivatives are effective non- nucleoside inhibitor of reverse transcriptase enzyme (NNRI) of HIV-1, several studies have been made by us and other groups in order to investigate the structure-activity relationships of these compounds and to improve their antiviral activity. 5 " 7 Results and Discussion In pursuit of our goal of finding new antiviral lead compounds, we report the synthesis of ethyl 4- (phenylamino)thieno[2,3-i]pyridine-5-carboxylate (6a-e) analogues and evaluate their anti-HSV-1 activity. The synthetic route used for preparing 4-(phenylamino)thieno[2,3-6]pyridines (6a-e) from 5- carboethoxy-4-chlorothieno[2,3-b]pyridine (5) is straightforward, and it was accomplished according to the reaction sequence outlined in Scheme l. 8 " 11 The bis-(2-thienylammonium)hexachlorostannate (1) was condensed with diethyl ethoxymethylenemalonate (2) to give ethyl a-carboethoxy-ß-(N-2-thienylammonium) acrylate (3). The cyclization of (3) was carried out by refluxing it in downtherm and isolating the ethyl 4- hydroxythienopyridine-3-carboxylate (4) by precipitating from petroleum ether. By NMR analysis it was possible to observe that the hidroxy tautomer (4) predominates over the quinolone, which was easily chlorinated in refluxing phosphorus oxychloride producing 5-carboethoxy-4-chlorothieno[2,3-i]pyridine (5). For producing the target compounds an equimolar mixture of anilines and (5) were refluxed for two hours producing the new products, ethyl 4-(phenylamino)thieno[2,3-%yridine-5-carboxylate (6a-e), were isolated Introduction R 407