Aldol-type compounds from water-soluble indole-3,4-diones: synthesis, kinetics, and antiviral properties
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Aldol-type compounds from water-soluble indole-3,4-diones: synthesis, kinetics, and antiviral properties Angela Scala · Massimiliano Cordaro · Antonino Mazzaglia · Francesco Risitano · Assunta Venuti · Maria Teresa Sciortino · Giovanni Grassi
Received: 22 January 2013 / Accepted: 22 April 2013 © Springer Science+Business Media Dordrecht 2013
Abstract A straightforward transformation of indole-3, 4-diones is reported. The reaction feasibility is evidenced by kinetic studies on a model substrate, revealing a double phase process with a first faster pseudo-first-order step (i.e., deprotonation of the dione and self-nucleophilic attack of the anion) and a subsequent slower dehydration of the intermediate. The overall process is faster at pH higher than the pK value of the investigated substrate. The biological relevance of new compounds has been assessed in vitro against herpes simplex virus type-1 (HSV-1), showing a more promising biological profile with respect to their precursors. Keywords Indoledione · Aldol condensation · Kinetics · Antiviral activity
Introduction The indole core is a ubiquitous substructure in many natural products and biological active molecules [1–3]. Indolebased compounds are reported to exhibit broad-spectrum chemotherapeutic properties such as antiviral, antitubercular, antifungal, and antibacterial activities [4]. A. Scala · A. Mazzaglia CNR-ISMN Istituto per lo Studio dei Materiali Nanostrutturati, V.le F. Stagno D’Alcontres 31, 98166 Messina, Italy M. Cordaro · F. Risitano · G. Grassi (B) Dipartimento di Scienze Chimiche, Università di Messina, V.le F. Stagno D’Alcontres 31, 98166 Messina, Italy e-mail: [email protected] A. Venuti · M. T. Sciortino Dipartimento di Scienze Biologiche e Ambientali, Università di Messina, V.le F. Stagno D’Alcontres 31, 98166 Messina, Italy
In the framework of our studies dealing with the design of poly functionalized N,o-heterocycles [5–12], we have recently reported [13] an unprecedented class of water soluble indole-3,4-diones as promising lead compounds for antiherpetic drugs development. Furthermore, these molecules have been successfully entrapped in amphiphilic β-cyclodextrin nanoparticles to increase bioavailability and modulate drug delivery [13]. Interestingly, our indoledione molecular architecture shares structural features with some inhibitors of cyclindependent kinases (CDKs) (Fig. 1) currently evaluated for therapeutic use against cancer, neurodegenerative disorders, and viral diseases (HCMV, HIV, HSV) [14]. In fact, although the search for CDKs inhibitors was initially directed toward applications against cancer, they are also evaluated currently for other indications, as CDKs regulate the cell division cycle, apoptosis, transcription, and differentiation. It is noteworthy that, over the past few years, CDKs inhibitors have been reported to prevent viral replication in vitro [14]. For the treatment of herpesvirus infections, at present, there are three classes of drugs licensed and all target viral DNA replication: (i) th
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