Research Article For reprint orders, please contact: reprints@futuremedicine.com Hydrazone, benzohydrazones and isoniazid-acylhydrazones as potential antituberculosis agents Elo´ısa G Sampiron 1 , Giovana F Costacurta 1 , Vanessa P Baldin 2 , Aryadne L Almeida 2 , Andressa L Ieque 1 , Nathally CS Santos 2 , Vanessa G Alves-Olher 3 , F´ abio Vandresen 4 , Ana CR Gimenes 3 , Vera LD Siqueira 2 , Katiany R Caleffi-Ferracioli 2 , Rosilene F Cardoso 1,2 & Regiane BL Scodro* ,1 1 Postgraduate Program in Health Sciences, State University of Maring ´ a, Maring ´ a, Paran ´ a, 87020-900, Brazil 2 Postgraduate Program in Bioscience & Physiopathology, State University of Maring´ a, Maring ´ a, Paran ´ a, 87020-900, Brazil 3 Department of Chemistry, Federal Institute of Paran´ a, Paranava´ı, Paran ´ a, 87703-536, Brazil 4 Department of Chemistry, Federal Technological University of Paran´ a, Londrina, Paran ´ a, 86057-970, Brazil *Author for correspondence: Fax: +55 44 3011 5376; rblscodro@uem.br Aim: To evaluate the potential of three benzohydrazones (1–3), four acylhydrazones derived from isoni- azid (INH-acylhydrazones) (4–7) and one hydrazone (8) as antituberculosis agents. Materials & methods: Inhibitory and bactericidal activities were determined for the reference Mycobacterium tuberculosis (Mtb) strain and clinical isolates. Cytotoxicity, drug combinations and ethidium bromide accumulation assays were also performed. Results: The tested compounds (1–8) presented excellent antituberculosis activity with surprisingly inhibitory (0.12–250 μg/ml) and bactericidal values, even against multidrug-resistant Mtb clinical isolates. Compounds showed high selectivity index, with values reaching 1833.33, and a lim- ited spectrum of activity. Some of the compounds (2 & 8) are also great inhibitors of bacillus efflux pumps. Conclusion: Benzohydrazones and INH-acylhydrazones may be considered scaffolds for the development of new anti-Mtb drugs. First draft submitted: 7 February 2019; Accepted for publication: 19 June 2019; Published online: 6 August 2019 Keywords: ADME • benzohydrazones • checkerboard • cytotoxicity • efflux pump • hydrazone • isoniazid- acylhydrazones • Mycobacterium tuberculosis • multidrug-resistant • REMA Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (Mtb) complex, is the leading cause of deaths among infectious diseases. Although it is a prehistoric disease, TB still presents alarming data, with around 1.3 million deaths per year, and an incidence of 10 million cases in 2017 alone [1]. The basic treatment schedule used for TB is composed of isoniazid (INH), rifampicin (RIF), ethambutol (EMB) and pyrazinamide (PZA). The treatment is well established but poorly accepted by patients due to its long time and many side effects. This leads to the high rates of multidrug-resistant (MDR, resistance to INH and RIF) and extensively-resistant mycobacteria (resistance to INH and RIF, plus any fluoroquinolone and at least one injectable second-line drug), whose numbers have become increasingly worrying [1]. One of the major mechanisms responsible for Mtb resistance to most drugs is the export of drugs by efflux pumps (EPs). EPs are proteins present in the bacteria wall capable of expelling compounds entering the bacillus. The search for compounds capable of acting as inhibitors of these EPs has increased, since they promote drug tolerance, and thus, can be used as an adjuvant in the treatment, improving the therapeutic schedule effectiveness [2,3]. Hydrazones and N-acylhydrazones are organic compounds classified as Schiff bases, with important antimy- cobacterial, antitumoral, antiviral and antiparasitic activities [4]. Compounds with hydrazone and N-acylhydrazone groups also have important anti-inflammatory properties [5], an important characteristic for the pathogenesis of TB. In order to improve the activity of some of these against specific pathogens, such as Mtb, several research groups have conjugated them with drugs already used for TB treatment. Great results have been found with INH derivatives, giving rise to selective and promising compounds [6,7]. Future Microbiol. (2019) 14(11), 981–994 ISSN 1746-0913 981 10.2217/fmb-2019-0040 C  2019 Future Medicine Ltd