Publications

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2-Amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine (compound S2242) represents the first antivirally active nucleoside analog with the side chain attached to the N-7 position of the purine ring. Compound S2242 strongly inhibits the in vitro replication of both herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) (50% effective concentration [EC50], 0.1 to 0.2 microgram/ml), varicella-zoster virus (EC50, 0.01 to 0.02 microgram/ml) and thymidine kinase (TK)-deficient strains of HSV (EC50, 0.4 microgram/ml) and varicella-zoster virus (EC50, 0.2 to 0.5 microgram/ml). Potent activity was also observed against murine cytomegalovirus (EC50, 1 microgram/ml), human cytomegalovirus (HCMV) (EC50, 0.04 to 0.1 microgram/ml), and human herpesvirus 6 (EC50, 0.0005 microgram/ml). Compound S2242 (i) was not cytotoxic to confluent Vero, HeLa, or human fibroblast cells at concentrations of > 100 micrograms/ml, (ii) proved somewhat more cytostatic to Vero, HEL, HeLa, and C127I cells than ganciclovir, and (iii) was markedly more cytostatic than ganciclovir to the growth of the human lymphocytic cell lines HSB-2 and CEM degrees. In contrast to ganciclovir, (i) compound S2242 proved not to be cytocidal to murine mammary carcinoma (FM3A) cells transfected with the HSV-1 or HSV-2 TK gene, (ii) exogenously added thymidine had only a limited effect on its anti-HSV-1 activity, and (iii) the compound was not phosphorylated by HSV-1-encoded TK derived from HSV-1 TK-transfected FM3A cells, indicating that the compound is not activated by a virally encoded TK. Compound S2242 inhibited (i) the expression of late HCHV antigens at an EC50 of 0.07 microgram/ml (0.6 microgram/ml for ganciclovir) and (ii) HCMV DNA synthesis at an EC50 of 0.1 microgram/ml (0.32 microgram/ml for ganciclovir), i.e., values that are close to the EC50S for inhibition of HCMV-induced cytopathogenicity. Neither ganciclovir nor S2242 had any effect on the expression of immediate-early HCMV antigens, which occurs before viral DNA synthesis. In time-of-addition experiments, S2242 behaved like ganciclovir and acyclovir; i.e., the addition of the drugs could be delayed until the onset of viral DNA synthesis.

A novel series of hybrid molecules with cholesterol and naphthalenesulfonic acid have been synthesized and evaluated for their inhibitory activity against myxoviruses (respiratory syncytial virus [RSV], influenza A and B virus), Naphthalenesulfonic acids (compounds 1–3) and cholesterols (compounds 4 and 5) did not inhibit myxovirus-induced cytopathic-ity. However, hybrid molecules (compounds 6 and 7) proved active against RSV and influenza A virus but not influenza B virus. The antiviral effects of the hybrid compounds 6 and 7 were comparable to those of dextran sulfate. Mixtures of naphthalenesulfonic acid and cholesteryl chloroformate (compounds 1 and 5 molecules, corresponding to the hybrid molecule 6; and compounds 2 and 5, corresponding to the hybrid molecule 7) did not show antiviral activity. The mode of action of the cholesterol-linked naphthalenesulfonic acids can be attributed to inhibition of virus-cell fusion (influenza A virus) or inhibition of both virus-cell binding and fusion (RSV).

In the design of the metrological atomic force microscope (mAFM), the commercial scanhead is adapted to reach a high thermal stability. To achieve this, an Invar support for the probe is kinematically connected to the aluminium commercial head. The interface between both parts allow for thermal expansion with minimum introduction of internal stress, while maintaining sufficient stiffness in the design. This paper describes and evaluates the novel design of the thermally stable probe mount. FEM-simulations of the thermal expansion show a minimum impact of the introduced stress on the accuracy of the mAFM.

In an attempt to determine some of the structural features of geiparvarin (1) that account for its cytostatic activity in vitro, a series of geiparvarin analogues (4a-g) modified in the 3(2H)-furanone moiety have been designed and synthesized. The preparation of 4a-g was achieved through a new approach to the 3(2H)-furanone ring based on the elaboration of isoxazole derivatives. Among these synthetic analogues, 4b, the 5-methyl-5-ethyl derivative, proved as active as 1 in inhibiting the proliferation of murine and human tumor cell lines in vitro. As a rule, substitutions at the C5 atom of the 3(2H)-furanone moiety of 1 slightly decreased the cytostatic activity of geiparvarin. Several geiparvarin analogues described in this study (i.e. the 5-methyl-5-ethyl derivative 4b, 3(2H)-furanimine 4c, 5-methyl derivative 4f, and 5-ethyl derivative 4g) showed such activity in vitro and deserve further investigation for their antitumor potentials in vivo.

There is an urgent need for the design and development of new and safer drugs for the treatment of human immunodeficiency virus (HIV) infection, specifically active against drug-resistant viral strains. Recently, sulfanyltriazole/tetrazole derivatives were reported as potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), with low nanomolar intrinsic activity against RT and submicromolar antiviral activity in HIV infected cells. In this review, the structural modifications, SAR analysis and docking studies of sulfanyltriazole/tetrazoles HIV-1 NNRTIs are discussed, and other interesting NNRTIs with the same or similar pharmacophore as the sulfanyltriazole/tetrazole derivatives are also presented and analyzed for their in SAR.