SYNTHESIS, TRYPANOCIDAL ACTIVITY AND DNA BINDING OF NEW BENZO[b][1,8]- NAPHTHYRIDONES DERIVATIVES

Abstract

A novel set of N-alkyl naphthyridone compounds has been prepared and characterized.These compounds have been compared to analogous 9-acridinones for a possible trypanocidal activity. With reference to this, naphthyridones seem to be more promising compounds than the 9-acridinone ones. INTRODUCTIONWithin the scope of the search of new trypanocidal agents (1-3) we have recently prepared and tested some 1,4-dimethoxy-9-(10H)-acridinone derivatives (4). As the naphtyridine nucleus is structurally related to the acridine one, we were also interested in preparing and investigating antiparasitic activity of some new benzo [b][1,8]-5-naphthyridone derivatives, substituted similarly as acridinones already tested. EXPERIMENTAL Synthesis, trypanocidal activity and DNA binding of new benzo [b] [ 1,8]-naphthyridones derivatives -ChemistryMelting points were determined in open capillary tubes on a Buchi-Tottoli apparatus and are given uncorrected. NMR spectra were recorded at 20.00 ± 0.1 °C, using a Bruker AM 200 spectrometer. Microanalyses were carried out using a Technicon CHN autoanalyzer.G6n6ral procedure for synthesis of compounds 1-8 (scheme 1) Procedure for compounds land 2.A mixture of freshly distilled aniline or properly substituted anilines (80 mmol), 2-chloro nicotonic acid (80 mmol), copper (0.8 g) and xylene (200 ml) is refluxed for 24 h with stirring.After filtration, the mixture is allowed to cool to room temperature. The precipitate obtained is recrystallized. Procedure for compounds 2_and_4Anthranilic acids 1 or 2 (10 mmol) are refluxed for 4 h with polyphosphoric acid in excess (more than 20 fold the weight of anthranilic acid). Then, the mixture is poured on ice and ammonia is slowly added. The precipitate obtained is recrystallized. Procedure for compounds 5 and_£A mixture of naphthyridone 2 or 4 (10 mmol), alkylating agent (15 mmol), and triethylbenzylammonium chloride hydrochloride (5 mmol), aqueous 50 % potassium hydroxide (50 ml), and toluene (100 ml) is refluxed for 24 h with stirring. Then, the organic layer is separated, washed with water, and dried with anhydrous sodium sulfate. After evaporation of solvent, crude product is recrystallized.Procedure for compound Ζ A mixture of £ (2 mmol) and 40 % hydrobromic acid (320 mmol), is refluxed for 4 h with stirring before being allowed to cool to room temperature. Solution is then neutralized with ammonia, with cooling to maintain the temperature at 0° C. The precipitate obtained is recrystallized.

An Efficient Synthesis of Pyrazolo[3,4-b]quinolin-3-amine and Benzo[b][1,8]naphthyridine Derivatives

“…Pyrazolo [3,4-b]quinoline derivatives are used as pharmaceutical agents and as inhibitors of oncogenic Ras [7,8]. Interesting pharmacological properties have also been associated with benzo[b] [1,8]naphthyridine derivatives, which posses antitumor, trypanocidal and DNA binding properties [9,10] and are antimicrobial agents [11]. In continuation of this work, we report herein a synthesis of pyrazolo [3,4-b]quinoline and benzo [b] [1,8]naphthyridine derivatives utilizing the hexahydroquinoline 10 as starting material.…”

Synthesis ofo-(Dimethylamino)aryl Ketones, Acridones, Acridinium Salts, and 1H-Indazoles by the Reaction of Hydrazones and Arynes

“…However, the pyridine-derived hydrazone 117 led to formation of the desired aza-acridone derivative 118 in a 48% yield (entry 13). The latter compound is a type of benzonaphthyridinone, some of which have shown antimicrobial, 35 trypanocidal, 36 and anticancer 37 activities. They have also been shown to reverse the multidrug resistance of tumor cells.…”

Synthesis of some New Schiff Bases and Hydrazones Containing Benzonaphthyridine/ Benzonaphthyridone Moiety

“…Ullmann synthesis involves the condensation of o-halobenzoic acid with substituted 2-aminopyridine in presence of cupric oxide and anhydrous potassium carbonate to give N-pyridylanthranilic acids (Jameel and Al-Hadedi, 2010). Cyclization of N-pyridylanthranilic acid can be achived by concentrated H 2 SO 4 (Acheson, 1973), polyphosphoric acid (PPA) (Meftah et al, 1994) and POCl 3 (Al-Hadedi, 2008) to give different types of tricyclic hetero compounds. The literatures showed that the benzonaphthyridine/ benzonaphthyridone derivatives have versatile biological activities such as antitumor (Chen et al, 1994), trypanocidal (Mefetah et al, 1994, antimicrobial (Tabart et al, 2001), antibacterial (Tabart et al, 2003), anticancer (Deady et al, 2003), anticolinesterase (Marco et al, 2004), antimalarial (Gorlitzer et al, 2007), anti-HSV-1 (Pincheiro et al, 2008), antifungal (Bhambi et al, 2009), anti-intestinal activity (Duan et al, 2011), and used as anti-inflammatory agent (Flockerzi et al, 2012).…”