Synthesis, biological evaluation, and molecular modeling studies of new 1,3,4-oxadiazole- and 1,3,4-thiadiazole-substitu
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Med Chem Res DOI 10.1007/s00044-012-0241-5
ORIGINAL RESEARCH
Synthesis, biological evaluation, and molecular modeling studies of new 1,3,4-oxadiazole- and 1,3,4-thiadiazole-substituted 4-oxo-4H-pyrido[1,2-a]pyrimidines as anti-HIV-1 agents Z. Hajimahdi • A. Zarghi • R. Zabihollahi M. R. Aghasadeghi
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Received: 15 February 2012 / Accepted: 14 September 2012 Ó Springer Science+Business Media New York 2012
Abstract A new series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives containing 1,3,4-oxadiazole and 1,3,4thiadiazole rings as a part of the metal chelation motif were synthesized and evaluated for their in vitro anti-HIV-1 activity. Most of the tested compounds displayed moderate inhibitory properties against HIV-1 virus (NL4-3) in Hela cell cultures. Compounds 11e and 11b exhibited the highest activity among the synthesized compounds with inhibition rate of 51 and 48 % at concentration of 100 lM, respectively. Molecular docking study using the later crystallographic data available for PFV integrase (IN) showed that the designed compounds bind into the active site of IN such that the keto oxygen atom at position of C-4 and nitrogen atom of thiadiazole or oxadiazole ring moiety chelate the Mg2? ion. Our results also showed that all tested compounds presented no significant cytotoxicity at concentration of 100 lM. Therefore, these compounds can provide a very good basis for the development of new hits. Keywords 4-Oxo-4H-pyrido[1,2-a]pyrimidines Oxadiazoles Thiadiazoles Anti-HIV-1 activity Molecular modeling
Z. Hajimahdi A. Zarghi (&) Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, P.O. Box 14155-6153, Tehran, Iran e-mail: [email protected] R. Zabihollahi M. R. Aghasadeghi Hepatitis and AIDS Department, Pasteur Institute of Iran, Tehran, Iran
Introduction Human immuno-deficiency virus type 1 (HIV-1) is the etiological agent that causes acquired immuno-deficiency syndrome (AIDS). HIV infection is a life-threatening health problem necessitating discovery of novel targets and new lead molecules. Studies in HIV biology have provided important information about the main steps of the virus life cycle which consists of viral entry, reverse transcription, integration, gene expression, virion assembly, budding, and maturation. HIV-1 encodes three enzymes that are essential for retroviral replication: reverse transcriptase (RT), protease, and integrase (IN) (Moyle et al., 2008). Although drugs targeting RT and protease are in wide use and have shown effectiveness particularly when employed in combination, these highly active antiretroviral therapies (HAART) still show important limitations. These are costs, occurrence of various side effects due to drug toxicity and most importantly, the loss of drug effectiveness over time caused by development of resistance, including multidrug resistance and cross-resistance (Barbaro et al., 2005). HIV-1 IN plays a central role in the insertion of viral DNA into the genome of host cells, which first catalyzes removal
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