351 ISSN 0326-2383 Acta Farm. Bonaerense 25 (3): 351-5 (2006) Recibido el 11 de mayo de 2005 Aceptado el 19 de febrero de 2006 Trabajos originales KEY WORDS: Antiviral agents, Chloroquine, Coxsackievirus, Heterocycles. PALABRAS CLAVE: Antivirales, Cloroquina, Coxsackievirus, Heterociclos. * Author to whom correspondence should be addressed: E-mail: ldias@vm.uff.br New Chloroquine Analogues as Antiviral Agents Luiza R.S. DIAS 1 *, Antonio C.C. FREITAS 1 , Dhammikka NANAYAKKARA 2,3 , James D. McCHESNEY 2,4 & Larry WALKER 2,3 1 Laboratório de Química Medicinal (LQMed), Faculdade de Farmácia, Universidade Federal Fluminense, Rua Mário Viana, 523 Santa Rosa - Niterói - RJ - ZIP 24241-000, Brazil 2 Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, USA. 3 National Center for Natural Products Research, School of Pharmacy, University of Mississippi, USA. 4 Present Address: Natural Product Chemistry and Development, NaPro BioTherapeutics, Inc., Boulder, CO, 80301 SUMMARY. Rhinoviruses and Enteroviruses (polio, coxsackie, echovirus) are the two types of picor- naviruses responsible for the high number of human viral infections as the common cold. Structure Activi- ty Relationship data about antiviral agents indicate the nitrogened heterocycles are present in several ac- tive compounds. Considering the antiviral activity of chloroquine, used as standard drug for the Coxsack- ievirus B-3, two new analogues were synthesized and evaluated as antiviral agents: N 4 -(3-methyl-1-phenyl- 1H-pyrazolo[3,4-b]pyridine)-N 1 ,N 1 -diethyl-1,4-pentanediamine [1] and N 4 -(quinaldine)-N 1 ,N 1 -diethyl-1,4- pentanediamine [2]. The compound [1] showed in vitro antiviral activity against Coxsackievirus. RESUMEN. “Nuevos Análogos de la Cloroquina como Agentes Antivirales”. Rinovirus y Enterovirus (polio, coxsackie, echovirus) son los dos tipos de picornavirus responsables del alto número de infecciones virales en humanos como el resfrío (o la gripe). Datos de Relación Estructura Actividad sobre antivirales indica que los he- terociclos nitrogenados están presentes en la mayoría de los compuestos activos. Considerando la actividad anti- viral de cloroquina, usada como droga estándar para el Coxsackievirus B-3, se sintetizaron y evaluaron dos aná- logos como agentes antivirales: N 4 -(3-metil-1-fenil-1H-pyrazolo[3,4-b]piridina)-N 1 ,N 1 -dietil-1,4-pentanediamina [1] y N 4 -(quinaldina)-N 1 ,N 1 -dietil-1,4-pentanediamina [2]. El compuesto [1] mostró actividad in vitro contra Cox- sackievirus. INTRODUCTION Viruses are microscopic parasitic organisms which infect all living cells. Viruses cause minor as well as major infections in the host. Acute vi- ral respiratory infections are the most common cause of the morbity around the world. Aden- ovirus, orthomyxovirus, paramyxovirus and pi- cornavirus family (rhinoviruses and enterovirus- es) are responsible for causing respiratory dis- eases. Some of the common diseases associated with such viruses are acute viral rhinitis, pharyn- gitis, laryngotracheobronchitis, pneumonitis, in- fluenza and parainfluenza 1,2 . The picornaviruses share structural features in their capsids. Their classification is based on physical properties (particle density and pH-sen- sitivity), serological relatedness and nucleotide sequence. There are 5 genera: aphthovirus, car- diovirus, enterovirus, hepatovirus and rhi- novirus. The enteroviruses genera are the most frequently detected etiologic organisms, which was traditionally divides into tree groups (polio, cosackie and echoviruses). The virus causing hepatitis A (hepatovirus) has similar and biologi- cal characteristics to the enteroviruses. They are non-enveloped RNA viruses that are stable in acidic pH 1,3,4 . The highest incidence of enteroviruses, espe- cially the coxsackieviruses, detected in infection human is the common cold. Considering the worldwide diffusion of respiratory diseases, these syndromes have relevant socioeconomic importance. Many efforts have been directed to- ward the identification of agents useful in their prophylaxis and therapy 1 . Nevertheless, at the present time, no therapeutic agents is licensed