In this work, 17 new N-acylhydrazone derivatives of amino acids have been evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv. The compounds 8b, 8e, 8f, 9a-d, and 10c exhibited an important minimum inhibitory concentration activity between 12.5 and 50 lg ⁄ mL, which can be compared with that of the tuberculostatic drug D-cycloserine (20 lg ⁄ mL). a Control and prevention of TB are major challenge as one-third of the world's population is infected with Mycobacterium (1). Some antibiotics employed on tuberculosis treatment affect the metabolism of bacterial cell wall construction, which is a very important cellular component surrounding the cell membrane, providing additional support and protection (2). Basically, it is comprised of three covalently linked substructures: mycolic acids, peptidoglycan, and arabinogalactan, which represent over 60% of cell dry weight (3). The peptidoglycan is formed by extensive chains of polysaccharides and amino acid residues. The D-cycloserine, a second-line drug for tuberculosis treatment, binds to the terminal portion of D-ala-D-ala of a peptide found in peptidoglycan precursors, interfering in the transpeptidation step (2,4).In our continuous search of new potent and safe antitubercular agents, we decided to synthesize a new class of N-acylhydrazone derivatives of amino acids as attractive D-cycloserine analogs. N-acylhydrazones are also described with a wide range of pharmacological activities, such as antibacterial agents (5-11).
Materials and MethodsGeneral procedures NMR spectra were obtained using a Bruker Avance spectrometer operating at 400 or 500 MHz ( 1 H) and 100 or 125 MHz ( 13 C), and a Bruker Avance DRX300 spectrometer operating at 300 MHz ( 1 H) and 75 MHz ( 13 C), in deuterated methanol, chloroform, or dimethylsulfoxide. Chemical shifts are reported in ppm relative to tetramethylsilane. Proton and carbon spectra were typically obtained at room temperature. Thin-layer chromatography was carried out on silica gel plates, using chloroform ⁄ methanol mixtures as eluents. For column chromatographic purification, column grade silica gel (0.063-0.200 mm mesh size) was employed. Mass spectra (ESI) were obtained on a ZQ electrospray spectrometer simple quadrupole. Melting points were determined using a Microquimica MQAPF-301 (Microquimica, Santa Catarina, Brazil) digital melting point apparatus.
ChemistryThe synthetic route used for the preparation of the title compounds is outlined in Scheme 1. The amino acids L-phenylalanine 1a, L-leucine 1b, and L-alanine 1c were employed as starting materials, and t-butoxycarbonyl (BOC) and benzyloxycarbonyl (Cbz) protecting groups were included in the core structures of 8a-j and 9a-d because of an intrinsic instability observed in non-protected derivatives.Compounds 8a-j, 9a-d, and 10a-c were prepared from the appropriate amino acids 1a-c, by esterification, leading to 2a-c, followed by N-protection to furnish 3a-c or 4a-c, using (BOC) 2 O or CbzCl, respectively. These compounds were conver...