DOI: 10.1002/cmdc.201100073 Structural Investigation of the Naphthyridone Scaffold: Identification of a 1,6-Naphthyridone Derivative with Potent and Selective Anti-HIV Activity Oriana Tabarrini,* [a] Serena Massari, [a] Luca Sancineto, [a] Dirk Daelemans, [b] Stefano Sabatini, [a] Giuseppe Manfroni, [a] Violetta Cecchetti, [a] and Christophe Pannecouque [b] Introduction Remarkable progress has been made in the treatment of HIV-1 infection/AIDS. However, the emergence of multidrug-resistant HIV strains and the inability of the current anti-HIV treatment to completely eradicate the virus in HIV-infected individuals de- mands new highly potent drugs capable of interfering with targets other those exploited by the anti-HIV drugs currently on the market. The 6-desfluoroquinolones (6-DFQs), developed by our group, [1–9] are innovative compounds that owe their potent anti-HIV activity to their ability to in- hibit the HIV-1 Tat-mediated transcription. This crucial step in HIV replication has not been clinically exploit- ed in anti-HIV therapy. The molecular target of 6- DFQs has not yet been fully identified. Indeed, al- though the lead compound acts by interfering selec- tively with the Tat–TAR complex formation, [1, 10] this is not strictly correlated to the antiviral activity and moreover, the same activity was not shown by other potent quinolone analogues. [9] Some evidence [1–9] (for example, different activities in various cell lines and the inability to select for resistance mutations), sug- gests that a host cellular factor or host cellular factor–viral component complex, involved in the Tat- mediated transcription, could be the target. Interfer- ing with host factors essential for viral replication is an attractive way of combating HIV-1 and avoiding the emergence of resistance. [11] Indeed, viral protein– cofactor interfaces are not only much less tolerant to mutations than the catalytic site of the highly variable viral enzyme, but they are particularly attractive targets for develop- ing selective drugs without compromising the normal process of transcriptional control at the cellular level of gene expres- sion. [12–14] Thus, the 6-DFQs possess beneficial properties that make them particularly attractive for further studies. Whereas we are attempting to identify the molecular target(s) that play a major role in their mechanism of action, our synthetic efforts have led to the identification of some very interesting compounds. The most exciting result was recently achieved by replacing the quinolone ring with the 1,8-naphthyridone core, a classic bioisosteric replacement also applied in the antibacterial qui- nolone field. [15, 16] Naphthyridone derivative HM13N (Figure 1) Building upon a large, previously reported series of anti-HIV 6- desfluoroquinolones endowed with a peculiar mechanism of action, the inhibition of Tat-mediated transcription, replace- ment of the quinolone nucleus with a naphthyridone core was shown to be very productive. In this work, the naphthyridone scaffold was investigated in depth by synthesizing various ana- logues. This led to the identification of NM13 as the most se- lective derivative obtained in MT-4 cells. It is the result of the successful combination of the 1,6-naphthyridone nucleus and the C7 benzothiazolpiperazine group, which, for the first time, not only grants potent anti-HIV activity but displays very high selectivity. Further studies aimed at a more thorough investiga- tion of the anti-HIV profile of this new derivative are in prog- ress. Figure 1. Structures of the compounds synthesized in this study starting from HM13N; for Ar, see Schemes 2 and 3. [a] Prof. O. Tabarrini, Dr. S. Massari, Dr. L. Sancineto, Dr. S. Sabatini, Dr. G. Manfroni, Prof. V. Cecchetti Dipartimento di Chimica e Tecnologia del Farmaco Università di Perugia, Via del Liceo 1, 06123 Perugia (Italy) Fax: (+ 39) 075-585-5115 E-mail : oriana.tabarrini@unipg.it [b] Dr. D. Daelemans, Prof. C. Pannecouque Rega Institute for Medical Research Katholieke Universiteit Leuven, 3000 Leuven (Belgium) ChemMedChem 2011, 6, 1249 – 1257  2011 Wiley-VCH Verlag GmbH& Co. KGaA, Weinheim 1249