worked for the smallpox eradi-cation programme in western Africa in 1962-1963 as a member of the staff of the W H O Regional Office for Africa. In 1964 he was transferred t o W H O Headquarters in Geneva, and in 1966 he joined the Smallpox Eradication unit, of which he was Chief from 1977 until 1984. He is now Director of the Kumamoto National Hospital in Japan and a member of the advisory group on international health of the Ministry of Health and Welfare of Japan. while at the Communicable Disease Center in the USA, was responsible in 1965-1 966 for the planning of the western and central African smallpox eradication-measles control programme, conducted with the support of the United States Agency for International Development. USSR from 1983 until his death in 1987. T h e authors alone are responsible for t h e views expressed i n t h i s publication. The World Health Organization welcomes such applications. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.

Smallpox and its eradication

The nature of metal complexes of heterocyclic thiosemicarbazones reported in the literature through 1989 have been reviewed with an emphasis on variations in stoichiometry and stereochemistry. A brief introduction is followed by a survey of the biological activity of the uncomplexed thiosemicarbazones. Next is a section on the chemical nature of thiosemicarbazones including a discussion of preparative methods, modes of coordination and isomerism. This is followed by a discussion of structural information and biological activity of the iron(III), iron(II), copper(II), cobalt(III), cobalt(II) and nickel(II) complexes of heterocyclic thiosemicarbazones. Short sections on the biological activity of other chelating thiosemicarbazones and metal complexes are also included.

Structural and physical correlations in the biological properties of transition metal heterocyclic thiosemicarbazone and S -alkyldithiocarbazate complexes

The front-line antituberculosis drug isoniazid (INH) and the related drug ethionamide (ETH) are prodrugs that upon activation inhibit the synthesis of mycolic acids, leading to bactericidal activity. Coresistance to INH and ETH can be mediated by dominant mutations in the target gene inhA, encoding an enoyl-ACP reductase, or by recessive mutations in ndh, encoding a type II NADH dehydrogenase (NdhII). To address the mechanism of resistance mediated by the latter, we have isolated novel ndh mutants of Mycobacterium smegmatis and Mycobacterium bovis BCG. The M. smegmatis ndh mutants were highly resistant to INH and ETH, while the M. bovis BCG mutants had low-level resistance to INH and ETH. All mutants had defects in NdhII activity resulting in an increase in intracellular NADH/NAD(+) ratios. Increasing NADH levels were shown to protect InhA against inhibition by the INH-NAD adduct formed upon INH activation. We conclude that ndh mutations mediate a novel mechanism of resistance by increasing the NADH cellular concentration, which competitively inhibits the binding of INH-NAD or ETH-NAD adduct to InhA.

Altered NADH/NAD+ Ratio Mediates Coresistance to Isoniazid and Ethionamide in Mycobacteria

Currently, there are a number of approved antiviral agents for use in the treatment of viral infections. However, many instances exist in which the use of a second antiviral agent would be beneficial because it would allow the option of either an alternative or a combination therapeutic approach. Accordingly, virus-encoded proteases have emerged as new targets for antiviral intervention. Molecular studies have indicated that viral proteases play a critical role in the life cycle of many viruses by effecting the cleavage of high-molecular-weight viral polyprotein precursors to yield functional products or by catalyzing the processing of the structural proteins necessary for assembly and morphogenesis of virus particles. This review summarizes some of the important general features of virus-encoded proteases and highlights new advances and/or specific challenges that are associated with the research and development of viral protease inhibitors. Specifically, the viral proteases encoded by the herpesvirus, retrovirus, hepatitis C virus, and human rhinovirus families are discussed.

Protease Inhibitors as Antiviral Agents

The investigation of the biological activity of thiosemicarbazones had as its origin Domagk's attempt to establish a relationship between the structure and antituberculous activity of a series of sulfathiadiazoles which were prepared by cyclizing the corresponding thiosemicarbazones (4). The end product, the thiadiazoles, proved uninteresting, but the intermediate thiosemicarbazones, which were tested by Behnisch and his group in Germany, were reported in 1946 to be strongly tuberculostatic in vivo (1, 4). Interest in compounds of this type was stimulated by the report of Hamre and her group at the Squibb Institute for Medical Research that certain of the aromatic aldehyde thiosemicarbazones possessed in vivo activity against vaccinia virus--both in embryonated eggs and in mice (3, 5, 6). The antivaccinial activity of this class of compounds in mice has been confirmed and extended by R. L. Thompson and his co-workers (8, 9, 10, 11) and in this laboratory. ~ Compounds capable of inhibiting virus multiplication, which presumably involves synthesis of nucleoprotein, are of interest as candidate anticancer agents. Thiosemicarbazones have been tested, therefore, for activity against several solid tumors and leukemias in mice. Metaand paranitrobenzaldehyde thiosemicarbazones were found to have weak but consistent activity against Adenocarcinoma 755, restricting tumor growth to 40-50 per cent of that in untreated controls at levels that did not result in weight loss or death of treated animals? Thiosemicarbazones appear to be

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Observations on the antileukemic activity of pyridine-2-carboxaldehyde thiosemicarbazone and thiocarbohydrazone.

Summaryp-Aminobenzaldehyde, 3-thiosemicarbazone (MC2343) caused a significant delay in death and survival of a small percentage of chick embryos and mice infected with vaccinia virus.At the concentrations tested this compound was inactive against the agent of meningopneumonitis, the vole rickettsia (Baker) and swine influenza virus.Preliminary results indicated that the p-acetamido analogue (Myvizone) was also active against vaccinia virus.

Jack Bernstein

Papers

Activity of p-Aminobenzaldehyde, 3-Thiosemicarbazone on Vaccinia Virus in the Chick Embryo and in the Mouse

The chemotherapy of experimental tuberculosis. I. The in vitro activity of thiosemicarbazides, thiosemicarbazones, and related compounds.

The chemotherapy of experimental tuberculosis. II. Thiosemicarbazones and analogues in experimental tuberculosis in the mouse.