Design, synthesis and docking studies of new furobenzopyranones and pyranobenzopyranones as photoreagent towards DNA and as antimicrobial agents

• Published in: European journal of medicinal chemistry 2010, Vol.45 (1), p.317-325
• Main Authors: Farag, Nahla A.H., El-Tayeb, Wafaa
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Anti-Infective Agents - chemical synthesis; Anti-Infective Agents - chemistry; Anti-Infective Agents - metabolism; Anti-Infective Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimicrobial activity; Bacteria - drug effects; Benzopyrans - chemical synthesis; Benzopyrans - chemistry; Benzopyrans - metabolism; Benzopyrans - pharmacology; Biological and medical sciences; Catalytic Domain; DNA - metabolism; DNA Gyrase - chemistry; DNA Gyrase - metabolism; Drug Design; Enzyme inhibitor; Furans - chemical synthesis; Furans - chemistry; Furans - metabolism; Furans - pharmacology; Furobenzopyranone; Furocoumarins; General aspects; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Photochemotherapeutic agents; Photoradiation therapy and photosensitizing agent; Photosensitizing activity; Photosensitizing Agents - chemical synthesis; Photosensitizing Agents - chemistry; Photosensitizing Agents - metabolism; Photosensitizing Agents - pharmacology; Pyranobenzopyranone; Topoisomerase II DNA gyrase B; Treatment with physical agents; Treatment. General aspects; Tumors
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2009.10.016

A number of new furobenzopyranones and pyranobenzopyranones carrying an electron- withdrawing function at the position 3 are synthesized in order to obtain new photoreagents towards DNA. Our interest in this study is to investigate the effect of introduction of electron withdrawing function on the position 3 of the benzo-á-pyranone ring of linear furobenzo-á-pyranone (5,8-dimethoxypsoralen) or angular pyranobenzo-á-pyranone on the biological activity, by preparing 3-cyano, carboxylic acid, carboxylic acid ester, acid hydrazide, thiosemicarbazide, or mercaptotriazole derivatives. 5-acetyl-6-hydroxybenzofuran, and 8-acetyl-7-hydroxy-4-phenylbenzopyranone are the key starting compounds on which 3-cyano-4-methylfurobenzopyranone and 3-cyano-4-methyl pyranobenzopyranone moieties were built respectively. The photobiological activity of the newly synthesized compounds was evaluated. It looks most promising for enhancement of photoreactivity of compounds towards DNA, and a certain effect was observed in the dark determining the antimicrobial activity. Compounds 5, 6, 7, 13, 14 exhibit potential photoreactivity towards DNA, while 3-mercaptotriazole derivatives 7, 14 possess only photosensitizing activity. To investigate the antimicrobial data on structural basis, molecular modelling and docking studies of the tested compounds into the crystal structure of topoisomerase II DNA Gyrase B complexed with the natural inhibitor bearing the coumarin moiety clorobiocin (1kzn), using Molsoft ICM 3.4-8C program was performed in order to predict the affinity and orientation of the synthesized compounds at the active site. The ICM score values and hydrogen bonds formed with the surrounding amino acids show good agreement with predicted binding affinities obtained by molecular docking studies as verified by antimicrobial screening, where compounds 5, 6, 13 were the most active compounds against Bacillus subtilis, Staphylococcus aureus, and Escherichia coli. Compound 13 has good affinity with the receptor and forms six hydrogen bonds with Asp-73, and two bonds with Thr-165, compound 6 has ICM score value −85.66 and forms one hydrogen bond with Asp-73, and three with Thr-165, and compound 5 has ICM score value −53 but forms one hydrogen bond with Asp-73, and four bonds with Thr-165 which may reveal the potent antimicrobial activity referred to the natural antimicrobial Clorobiocin which forms two hydrogen bonds with Asp-73 and three with Thr-165. Binding mode of compound 13 in the