Potential Tuberculostatic Agents. Topliss Application on Benzoic Acid [(5-Nitro-thiophen-2-yl)-methylene]-hydrazide Series Daniela G. Rando, a Dayse N. Sato, b Leonardo Siqueira, c Alberto Malvezzi, c Clarice Q. F. Leite, d Antonia T. do_Amaral, c Elizabeth I. Ferreira a and Leoberto C. Tavares a, * a Fac. de Cie ˆncias Farmace ˆuticas, USP, Av. Prof. Lineu Prestes, 580, Sa ˜o Paulo-SP 05508-900, Brazil b Instituto Adolfo Lutz, R. Minas Gerais, 887, Ribeira ˜o Preto-SP 14085-410, Brazil c Instituto de Quı´mica, USP, Av. Prof. Lineu Prestes, 748, Sa ˜o Paulo-SP 05508-900, Brazil d Fac. de Cie ˆncias Farmace ˆuticas, UNESP, Rod. Araraquara/Jau ´, Km 1, Araraquara-SP 14801-902, Brazil Received 24 May 2001; accepted 21 August 2001 Abstract—Nitroaromatic compounds such as nifuroxazide are used in many human enteropathogenic bacteria infections without causing an increase in the plasmidial antibiotic resistance of the aerobic Gram-negative intestinal Enterobacteriaceae. For these reasons, these compounds have been synthesized using the rational approach of Topliss’ decision tree. Generally, this approach allows us to obtain the most active derivative from the series in a few steps. These compounds were tested against Mycobacterium tuberculosis in vitro and the most active of the series identified. A new lead for potential tuberculostatic activity has been predicted and will be used in further QSAR studies. # 2002 Elsevier Science Ltd. All rights reserved. Introduction Tuberculosis remains a major public health issue at the beginning of the 21st century. Only in the last decade, TB caused nearly 3 million deaths annually. The esti- mated 8.8 million new cases every year correspond to 52,000 deaths per week or more than 7000 each day. In developing countries tuberculosis is a leading cause of morbidity and mortality (Fig. 1). War, famine, home- lessness and the spread of the HIV epidemic has sig- nificantly contributed to the worsening of the situation. 1 Co-infection with HIV has been responsible for the changes in the TB epidemiologic situation and also for the emergence of multidrug-resistant strains. 2 Because of this critical situation, much effort has been directed to the design of new drugs for tuberculosis therapeutics. Nitroaromatic compounds, such as nifuroxazide, have been used in many human enteropathogenic bacterial infections without causing an increase in the plasmidial antibiotic resistance of the aerobic Gram-negative intestinal Enterobacteriaceae. It is known that reduction of the nitro group is essential for the biological activity of these compounds and this may be responsible for the production of free radicals which could act on DNA. 3 Nitrothiophenes have already been tested against para- sitic infections and have demonstrated good results against Entamoeba histolytica, Trichomonas vaginalis, Leishmania tropica and L. infantum. Structure–activity studies suggested that an increase in conjugation on the thiophenic moiety leads to an increase in biological activity. 4 Considering the urgent need for chemotherapeutical alternatives against tuberculosis, particularly after the emergence of multidrug-resistant strains, and in view of the high activity shown by nifuroxazide, as already men- tioned, the objective of this work was to obtain the most active derivative from the benzoic acid 5-nitro-thiophen-2- yl)-methylene]-hydrazides series, nifuroxazide analogues. For this purpose we have applied Topliss’ methodology 5 to a set of nitrothiophen analogues (Fig. 2). All com- pounds have been synthesized and their activity eval- uated against Mycobacterium tuberculosis Rv strain. The fundamental structure is a nitrofurane analog, designed by classical bioisosterism between the oxygen and the sulfur atom ring. 0968-0896/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved. PII: S0968-0896(01)00313-3 Bioorganic & Medicinal Chemistry 10 (2002) 557–560 *Corresponding author. Tel.: +55-11-3818-3693; fax: +55-11-3815- 6386; e-mail: leoberto@usp.br