Novel antiviral benzofuran-transition metal complexes.
(5-(1H-benzo[d]imidazol-2-yl)-1H-pyrrol-3-yl)(6-hydroxy-4,7-dimethoxybenzofuran-5-yl)methanone (4) and 3-(6-hydroxy-4,7-dimethoxybenzofuran-5-carbonyl)-6H-pyrimido[1,6-a]pyrimidine-6,8(7H)-dione (5) were synthesized by the reaction of 4,7-dimethoxy-5-oxo-5H-furo[3,2-g]chromene-6-carbaldehyde (1) with (1H-benzo[d]imidazol-2-yl)methanamine dihydrochloride and 4-amino-2,6-dihydroxypyrimidine, respectively, via ROR in the presence of alcoholic KOH. The metal complexes 6-9 of compound 4; H(2)L(1) with (CuCl(2), FeCl(3), ZnCl(2), and LaCl(3)) and the metal complexes 10-13 of compound 5; H(2)L(2) with (CuCl(2), FeCl(3), CoCl(2) and LaCl(3)) were synthesized to form 1:1 or 1:2 (metal: ligand) complexes. The HIV inhibitory activity of all new compounds was tested. The EC(50) values showed that, all of tested compounds were more potent than Atevirdine. Moreover, the benzoimidazolylpyrrole derivative 4 (EC(50)=9x10(-6)muM) had higher therapeutic index than the standard. The HIV-1 RT inhibitory activity showed that all of the tested compounds showed significant potency but none of them showed higher activity than Atevirdine. The HCV NS3-4A protease inhibitor activity of the tested compounds revealed that the complex formation had great positive effect on the bioactivity, where the Fe-complex 7 was the most potent compound with higher therapeutic index than VX-950, the standard. Also, the cytotoxicity of the synthesized compounds on hepatocyte cell line, showed that Cu-complex 10 was the most potent compound with potency nearly to that of the standard.
Galal
Shadia A
SA
Division of Pharmaceutical and Drug Industries, Department of Chemistry of Natural and Microbial Products, National Research Center, Dokki, Cairo 12622, Egypt. sh12galal@yahoo.com
Abd El-All
Amira S
AS
Hegab
Khaled H
KH
Magd-El-Din
Asmaa A
AA
Youssef
Nabil S
NS
El-Diwani
Hoda I
HI
D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D001572:Benzofurans / Q000737:chemistry*; D015195:Drug Design; D006678:HIV / Q000187:drug effects / Q000201:enzymology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006878:Hydroxides / Q000737:chemistry; D007928:Lethal Dose 50; D008024:Ligands; D008958:Models, Molecular; D009584:Nitrogen / Q000737:chemistry; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D010084:Oxidation-Reduction; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D011487:Protein Conformation; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D013057:Spectrum Analysis; D028561:Transition Elements / Q000737:chemistry*
D000998:Antiviral Agents; D001572:Benzofurans; D006878:Hydroxides; D008024:Ligands; D009942:Organometallic Compounds; D011480:Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D028561:Transition Elements; C031356:hydroxide ion; D054303:HIV Reverse Transcriptase; C105430:benzofuran; D009584:Nitrogen