Yakini Brandy

Antitrypanosomal activities and cytotoxicity of some novel imido-substituted 1,4-naphthoquinone derivatives.

The antitrypanosomal activities, cytotoxicity, and selectivity indices of eleven imido-substituted 1,4-naphthoquinone derivatives and nifurtimox have been studied. Compared to nifurtimox (IC50 = 10.67 μM), all the imido-naphthoquinone analogs (IMDNQ1-IMDNQ11) are more potent on Trypanosoma cruzi with IC50 values ranging from 0.7 μM to 6.1 μM (p < 0.05). Studies of the cytotoxic activities of these compounds on a Balb/C 3T3 mouse fibroblast cell line revealed that four of these compounds, IMDNQ1, IMDNQ2, IMDNQ3, and IMDNQ10 displayed selectivity indices of 60.25, 53.97, 31.83, and 275.3, respectively, rendering them significantly (p < 0.05) more selective in inhibiting the parasite growth than nifurtimox (selectivity index = 10.86).

N-(3-Bromo-1,4-dioxo-1,4-dihydro-2-naphth-yl)-2-chloro-N-(2-chloro-benzoyl)benzamide.

The title compound, C24H12BrCl2NO4, was synthesized from 2-amino-3-bromo-1,4-naphthoquinone and 2-chlorobenzoyl chloride. The crystal structure shows that each of the chlorophenyl rings is inclined at about 60° to the naphthoquinone ring system. The two chlorophenyl rings adopt a conformation that ensures that chlorine substituents are anti so as to reduce electronic repulsion. An examination of the packing shows close O⋯Br and Cl⋯Cl contacts of 2.947 (2) and 3.346 (1) Å, respectively. In addition, the molecules are linked by weak intermolecular C—H⋯O and C—H⋯Cl interactions.

2-Chloro-3-(4-chloro­benzamido)-1,4-naphthoquinone

The naphthoquinone ring is almost perpendicular [dihedral angle 71.02 (3)°] to the phenyl group of the title compound, C17H9Cl2NO3, while the dihedral angle between the amide group and the 4-chlorophenyl ring is 21.9 (2)°. The conformation of the N—H and C=O bonds are anti to each other. N—H⋯Cl hydrogen bonds link the molecules into chains in the a-axis direction. In addition, these chains are linked by weak intermolecular C—H⋯O interactions.

Novel drug design for Chagas disease via targeting Trypanosoma cruzi tubulin: Homology modeling and binding pocket prediction on Trypanosoma cruzi tubulin polymerization inhibition by naphthoquinone derivatives.

Chagas disease, also called American trypanosomiasis, is a parasitic disease caused by Trypanosoma cruzi (T. cruzi). Recent findings have underscored the abundance of the causative organism, (T. cruzi), especially in the southern tier states of the US and the risk burden for the rural farming communities there. Due to a lack of safe and effective drugs, there is an urgent need for novel therapeutic options for treating Chagas disease. We report here our first scientific effort to pursue a novel drug design for treating Chagas disease via the targeting of T. cruzi tubulin. First, the anti T. cruzi tubulin activities of five naphthoquinone derivatives were determined and correlated to their anti-trypanosomal activities. The correlation between the ligand activities against the T. cruzi organism and their tubulin inhibitory activities was very strong with a Pearsons r value of 0.88 (P value <0.05), indicating that this class of compounds could inhibit the activity of the trypanosome organism via T. cruzi tubulin polymerization inhibition. Subsequent molecular modeling studies were carried out to understand the mechanisms of the anti-tubulin activities, wherein, the homology model of T. cruzi tubulin dimer was generated and the putative binding site of naphthoquinone derivatives was predicted. The correlation coefficient for ligand anti-tubulin activities and their binding energies at the putative pocket was found to be r=0.79, a high correlation efficiency that was not replicated in contiguous candidate pockets. The homology model of T. cruzi tubulin and the identification of its putative binding site lay a solid ground for further structure based drug design, including molecular docking and pharmacophore analysis. This study presents a new opportunity for designing potent and selective drugs for Chagas disease.

N-(3-Bromo-1,4-dioxo-1,4-dihydro-2-naphth-yl)-4-fluoro-N-(4-fluoro-benzo-yl)benzamide.

In the title compound, C24H12BrF2NO4, synthesized from 2-amino-3-bromo-1,4-naphthoquinone and 4-fluorobenzoyl chloride, the two p-fluorophenyl rings are inclined at 73.9 (1) and 73.6 (1)° to the naphthoquinone ring system. The two imido carbonyl O atoms are anti to each other, while the fluorophenyl rings are located opposite each other, connected to the imide group in a funnel-like arrangement. This conformation allows the fluorine groups be oriented slightly away from each other. An examination of the packing shows a close intermolecular F⋯O contact of 2.982 (5) Å and a Br⋯O contact of 2.977 (4) Å. In addition, the molecules are linked by weak intermolecular C—H⋯O and C—H⋯F interactions.

Synthesis and characterization of novel unsymmetrical and symmetrical 3-halo- or 3-methoxy-substituted 2-dibenzoylamino-1,4-naphthoquinone derivatives.

Symmetrical and unsymmetrical 3-halo- or 3-methoxy- substituted 2-dibenzoylamino-1,4-naphthoquinone analogs were synthesized with an average yield of 45% via sodium hydride promoted bis-acylation of 2-amino-3-chloro-1,4-naphthoquinone, 2-amino-3-bromo-1,4-naphthoquinone and 2-amino-3-methoxy-1,4-naphthoquinone.

N-Benzoyl-N-(1,4-dioxonaphthalen-2-yl)benzamide

The title molecule, C24H15NO4, crystallizes with two molecules in the asymmetric unit (Z′ = 2). For both molecules, the two amide groups are not coplanar, as the dihedral angles of the respective NCO groups are similar at 50.37 (14) and 51.22 (13)°. However, the orientations of the substituent phenyl rings with the central naphthalene system are significantly different for the two molecules; for one molecule, these dihedral angles are 80.29 (3) and 80.95 (4)°, while for the second molecule they are 86.63 (3) and 72.82 (4)°. The crystal packing shows the molecules to be linked by weak C—H⋯O interactions.

N-(1,4-Dioxo-1,4-dihydro-naphthalen-2-yl)benzamide.

The title compound, C17H11NO3, was an intermediate synthesized during bisacylation of 2-amino-1,4-naphthoquinone with benzoyl chloride. A mixture of block- and needle-shaped crystals were obtained after column chromatography. The block-shaped crystals were identified as the imide and the needles were the title amide. The naphthoquinone scaffold is roughly planar (r.m.s. deviation = 0.047 Å for the C atoms). The N—H and C=O bonds of the amide group are anti to each other. A dihedral angle between the naphthoquinone ring system and the amide group of 3.56 (3)°, accompanied by a dihedral angle between the amide group and the phenyl group of 9.51 (3)°, makes the naphthoquinone ring essentially coplanar with the phenyl ring [dihedral angle = 7.12 (1)°]. In the crystal, molecules are linked by a weak N—H⋯O hydrogen bond and by two weak C—H⋯O interactions leading to the formation of zigzag chains along [010].

2-Chloro-N-(2-chloro­benzo­yl)-N-(2-ethyl-4-oxo-3,4-di­hydro­quinazolin-3-yl)benzamide

In the title compound, C24H17Cl2N3O3, the quinazolinone ring system is close to planar (r.m.s. deviation = 0.0132 Å), with the imide unit almost perpendicular to it, subtending a dihedral angle of 89.1 (1)°. However, the imide unit itself is not planar, the dihedral angle between the two O=C—N components being 34.6 (1)°. The dihedral angle between the two chlorobenzene rings is 40.50 (7)°, while the angles between these rings and the imide moiety are 54.6 (1) and 58.2 (1)°, respectively. The dihedral angles between the 2-chlorophenyl rings and the quinazolinone ring system are 48.77 (5) and 32.92 (7)° for rings A and B, respectively. In the crystal, weak C—H⋯O interactions link the molecules into a three-dimensional array.