BVDU [(E)-5-(2-bromovinyl)-2′-deoxyuridine) is an extremely potent and selective inhibitor of HSV 1 (herpes simplex virus type 1) and VZV (varicella zoster virus) replication: in primary rabbit kidney and/or human diploid fibroblast cultures these viruses are inhibited at a drug concentration of about 0.01 µg/ml (0.03 µM). The selective antiherpes activity of BVDU resides in a specific inhibition of viral DNA synthesis, which, in turn, depends on at least two factors: (i), phosphorylation of BVDU by the virus-encoded dThd (deoxythymidine) kinase and, (ii), inhibition of the virus-induced DNA polymerase by the resulting BVDUTP (BVDU 5′-triphosphate). Both viral enzymes appear to contribute to the selective antiherpes action of BVDU. While BVDUTP is a specific inhibitor of HSV 1 DNA polymerase, it remains to be established whether it can also serve as substrate for this enzyme. Unlike 5-halogenated deoxyuridines [i.e. IDU (5-iodo-2′-deoxyuridine)], BVDU does not induce the production of oncogenic RNA viruses in mouse (i.e. BALB/3T3) cell lines.
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This review article presents the fourth part (part D) in the series of stories on antiviral drug discovery. The stories told in part D focus on: (i) the cyclotriazadisulfonamide compounds; (ii) the {5-[(4-bromophenylmethyl]-2-phenyl-5H-imidazo[4,5-c]pyridine} compounds; (iii) (1H,3H-thiazolo[3,4-a]benzimidazole) derivatives; (iv) T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) and (v) its structurally closely related analogue pyrazine 2-carboxamide (pyrazinamide); (vi) new strategies for the treatment of hemorrhagic fever virus infections, including, as the most imminent, (vii) dengue fever, (viii) the veterinary use of acyclic nucleoside phosphonates; (ix) the potential (off-label) use of cidofovir in the treatment of papillomatosis, particularly RRP (recurrent respiratory papillomatosis); and (x) finally, the prophylactic use of tenofovir to prevent HIV infections.
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Considering the undesirable metabolic stability of our recently identified NNRTI <b>5</b> (<i>t</i><sub>1/2</sub> = 96 min) in human liver microsomes, we directed our efforts to improve its metabolic stability by introducing a new favorable hydroxymethyl side chain to the C-5 position of pyrimidine. This strategy provided a series of novel methylol-biphenyl-diarylpyrimidines with excellent anti-HIV-1 activity. The best compound <b>9g</b> was endowed with remarkably improved metabolic stability in human liver microsomes (<i>t</i><sub>1/2</sub> = 2754 min), which was about 29-fold longer than that of <b>5</b> (<i>t</i><sub>1/2</sub> = 96 min). This compound conferred picomolar inhibition of WT HIV-1 (EC<sub>50</sub> = 0.9 nmol/L) and low nanomolar activity against five clinically drug-resistant mutant strains. It maintained particularly low cytotoxicity (CC<sub>50</sub> = 264 μmol/L) and good selectivity (SI = 256,438). Molecular docking studies revealed that compound <b>9g</b> exhibited a more stable conformation than <b>5</b> due to the newly constructed hydrogen bond of the hydroxymethyl group with E138. Also, compound <b>9g</b> was characterized by good safety profiles. It displayed no apparent inhibition of CYP enzymes and hERG. The acute toxicity assay did not cause death and pathological damage in mice at a single dose of 2 g/kg. These findings paved the way for the discovery and development of new-generation anti-HIV-1 drugs.
Substitution on the alpha position of thymidine with methylthio (3) and methylsulfonyl (5) groups gave antiviral agents that were specific and relatively nontoxic inhibitors of herpes simplex virus replication in cell culture. The thioether (3) was effective against both types 1 and 2 of herpes simplex virus, whereas the activity of the sulfone derivative (5) was restricted to herpes simplex virus type 1. The sulfoxide derivative 1-(2-deoxy-beta-D-ribofuranosyl)-alpha-(methylsulfinyl)thymine (4) was inactive as an antiviral agent. The 5'-phosphates of these three thymidine derivatives were relatively potent inhibitors of thymidylate synthetase (Ki values range from 7.8 to 1.9 microM). It is improbable that the inhibition of this enzyme accounts for the anti-herpes activity of compounds 3 and 5.
