Heterocyclic Compounds as Selective Inhibitors of Human Cytomegalovirus

Townsend, Leroy B.

Abstract

This proposal outlines several specific areas for the development of an agent to specifically treat HCMV infections. The target compounds will be elected on the basis of the structure activity relationships which have already been established from current and previous studies in our laboratory. Several areas of research are proposed and the specific aims for the next five years include the following: the synthesis of some polysubstituted benzimidazoles and imidazoles and their corresponding nucleosides and nucleoside analogs based on structure activity relationships derived from structurally related compounds. The synthesize of a few select 5-bromotubercidin and thiosangivamycin analogs is proposed. Synthesis of selected polysubstituted benzimidazole carbamates, unrelated to the above polysubstituted benzimidazoles, using a compound discovered through our very limited screen involving compounds selected at random from our previous synthetic investigations, as our focal point. The in vitro evaluations from Professors Drach, Lopatin and Kern's laboratories will be used to direct the chemical modifications in each new area of potential agents. All of these studies should provide some insights into the modifications which will effect an increase in the selectivity of these compounds against HCMV.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Allergy and Infectious Diseases (NIAID)
• Type: Research Program--Cooperative Agreements (U19)
• Project #: 5U19AI031718-06
• Application #: 5205486
• Support Year: 6
• Fiscal Year: 1996

Publications

Chen, Jiong J; Wei, Yuan; Williams, John D et al. (2005) Design, synthesis, and antiviral evaluation of some polyhalogenated indole C-nucleosides. Nucleosides Nucleotides Nucleic Acids 24:1417-37

Williams, John D; Drach, John C; Townsend, Leroy B (2005) Synthesis and antiviral activity of some 2-substituted 3-formyl- and 3-cyano-5,6-dichloroindole nucleosides. Nucleosides Nucleotides Nucleic Acids 24:1613-26

Migawa, Michael T; Drach, John C; Townsend, Leroy B (2005) Design, synthesis and antiviral activity of novel 4,5-disubstituted 7-(beta-D-ribofuranosyl)pyrrolo[2,3-d][1,2,3]triazines and the novel 3-amino-5-methyl-1-(beta-D-ribofuranosyl)- and 3-amino-5-methyl-1-(2-deoxy-beta-D-ribofuranosyl)-1,5-dihydro-1,4,5,6,7 J Med Chem 48:3840-51

Kern, Earl R; Hartline, Caroll B; Rybak, Rachel J et al. (2004) Activities of benzimidazole D- and L-ribonucleosides in animal models of cytomegalovirus infections. Antimicrob Agents Chemother 48:1749-55

Williams, John D; Chen, Jiong J; Drach, John C et al. (2004) Design, synthesis, and antiviral activity of certain 3-substituted 2,5,6-trichloroindole nucleosides. J Med Chem 47:5753-65

Chien, Tun-Cheng; Saluja, Sunita S; Drach, John C et al. (2004) Synthesis and antiviral evaluation of polyhalogenated imidazole nucleosides: dimensional analogues of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole. J Med Chem 47:5743-52

Williams, John D; Ptak, Roger G; Drach, John C et al. (2004) Synthesis, antiviral activity, and mode of action of some 3-substituted 2,5,6-trichloroindole 2'- and 5'-deoxyribonucleosides. J Med Chem 47:5773-82

Komazin, Gloria; Townsend, Leroy B; Drach, John C (2004) Role of a mutation in human cytomegalovirus gene UL104 in resistance to benzimidazole ribonucleosides. J Virol 78:710-5

Evers, David L; Komazin, Gloria; Ptak, Roger G et al. (2004) Inhibition of human cytomegalovirus replication by benzimidazole nucleosides involves three distinct mechanisms. Antimicrob Agents Chemother 48:3918-27

Porcari, Anthony R; Townsend, Leroy B (2004) An improved total synthesis of triciribine: a tricyclic nucleoside with antineoplastic and antiviral properties. Nucleosides Nucleotides Nucleic Acids 23:31-9