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Article

Novel Bifunctional Quinolonyl Diketo Acid Derivatives as HIV-1 Integrase Inhibitors: Design, Synthesis, Biological Activities, and Mechanism of Action

Supporting Info

Roberto Di Santo,*^† Roberta Costi,^† Alessandra Roux,^† Marino Artico,^† Antonio Lavecchia,*^‡ Luciana Marinelli,^‡ Ettore Novellino,^‡ Lucia Palmisano,^§ Mauro Andreotti,^§ Roberta Amici,^§ Clementina Maria Galluzzo,^§ Lucia Nencioni, Anna Teresa Palamara, Yves Pommier, and Christophe Marchand

Istituto PasteurFondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, and Istituto di Microbiologia, Universit di Roma La Sapienza, P. le A. Moro 5, I-00185 Roma, Italy, Dipartimento del Farmaco, Istituto Superiore di Sanit, Viale Regina Elena 299, I-00161 Roma, Italy, Dipartimento di Chimica Farmaceutica e Tossicologica, Universit di Napoli Federico II, via D. Montesano 49, I-80131 Napoli, Italy, and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute Building 37, Room 5068, National Institutes of Health, Bethesda, Maryland 20892-4255

J. Med. Chem., 2006, 49 (6), pp 1939–1945

DOI: 10.1021/jm0511583

Publication Date (Web): February 17, 2006

To whom correspondence should be addressed. R.D.S.: phone and fax, +39-6-49913150; e-mail, roberto.disanto@uniroma1.it. A.L.: phone and fax, +39-81-678613; e-mail, lavecchi@unina.it.

†

Dipartimento di Studi Farmaceutici, Istituto Superiore di Sanità.

‡

Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli “Federico II”.

Dipartimento del Farmaco, Instituto Superiore di Sanità.

Istituto di Microbiologia, Università di Roma “La Sapienza”.

Laboratory of Molecular Pharmacology, National Cancer Institute.

Abstract

The virally encoded integrase protein is an essential enzyme in the life cycle of the HIV-1 virus and represents an attractive and validated target in the development of therapeutics against HIV infection. Drugs that selectively inhibit this enzyme, when used in combination with inhibitors of reverse transcriptase and protease, are believed to be highly effective in suppressing the viral replication. Among the HIV-1 integrase inhibitors, the β-diketo acids (DKAs) represent a major lead for anti-HIV-1 drug development. In this study, novel bifunctional quinolonyl diketo acid derivatives were designed, synthesized, and tested for their inhibitory ability against HIV-1 integrase. The compounds are potent inhibitors of integrase activity. Particularly, derivative 8 is a potent IN inhibitor for both steps of the reaction (3‘-processing and strand transfer) and exhibits both high antiviral activity against HIV-1 infected cells and low cytotoxicity. Molecular modeling studies provide a plausible mechanism of action, which is consistent with ligand SARs and enzyme photo-cross-linking experiments.

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