RESUMEN
Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains the leading cause of death from a bacterium in the world. The global prevalence of clinically relevant infections with opportunistically pathogenic non-tuberculous mycobacteria (NTM) has also been on the rise. Pharmacological treatment of both TB and NTM infections usually requires prolonged regimens of drug combinations, and is often challenging because of developed or inherent resistance to common antibiotic drugs. Medicinal chemistry efforts are thus needed to improve treatment options and therapeutic outcomes. Nα-aroyl-N-aryl-phenylalanine amides (AAPs) have been identified as potent antimycobacterial agents that target the RNA polymerase with a low probability of cross resistance to rifamycins, the clinically most important class of antibiotics known to inhibit the bacterial RNA polymerase. In this review, we describe recent developments in the field of AAPs, including synthesis, structural characterization, inâ vitro microbiological profiling, structure-activity relationships, physicochemical properties, pharmacokinetics and early cytotoxicity assessment.
Asunto(s)
Amidas , ARN Polimerasas Dirigidas por ADN , Fenilalanina , Amidas/química , Amidas/farmacología , Amidas/síntesis química , ARN Polimerasas Dirigidas por ADN/antagonistas & inhibidores , ARN Polimerasas Dirigidas por ADN/metabolismo , Fenilalanina/farmacología , Fenilalanina/química , Fenilalanina/síntesis química , Fenilalanina/análogos & derivados , Humanos , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/enzimología , Relación Estructura-Actividad , Antituberculosos/farmacología , Antituberculosos/química , Antituberculosos/síntesis química , Estructura Molecular , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis químicaRESUMEN
The title compound, 3-[(benzo-1,3-dioxol-5-yl)amino]-4-methoxycyclobut-3-ene-1,2-dione, C12H9NO5 (3), is a precursor to an antimycobacterial squaramide. Block-shaped crystals of a monoclinic form (3-I, space group P21/c, Z = 8, Z' = 2) and needle-shaped crystals of a triclinic form (3-II, space group P-1, Z = 4, Z' = 2) were found to crystallize concomitantly. In both crystal forms, R22(10) dimers assemble through N-H...O=C hydrogen bonds. These dimers are formed from crystallographically unique molecules in 3-I, but exhibit crystallographic Ci symmetry in 3-II. Twinning by pseudomerohedry was encountered in the crystals of 3-II. The conformations of 3 in the solid forms 3-I and 3-II are different from one another but are similar for the unique molecules in each polymorph. Density functional theory (DFT) calculations on the free molecule of 3 indicate that a nearly planar conformation is preferred.
RESUMEN
Nα-aroyl-N-aryl-phenylalanine amides (AAPs) are RNA polymerase inhibitors with activity against Mycobacterium tuberculosis and non-tuberculous mycobacteria. We observed that AAPs rapidly degrade in microsomal suspensions, suggesting that avoiding hepatic metabolism is critical for their effectiveness inâ vivo. As both amide bonds are potential metabolic weak points of the molecule, we synthesized 16 novel AAP analogs in which the amide bonds are shielded by methyl or fluoro substituents in close proximity. Some derivatives show improved microsomal stability, while being plasma-stable and non-cytotoxic. In parallel with the metabolic stability studies, the antimycobacterial activity of the AAPs against Mycobacterium tuberculosis, Mycobacterium abscessus, Mycobacterium avium and Mycobacterium intracellulare was determined. The stability data are discussed in relation to the antimycobacterial activity of the panel of compounds and reveal that the concept of steric shielding of the anilide groups by a fluoro substituent has the potential to improve the stability and bioavailability of AAPs.
Asunto(s)
Antibacterianos , Mycobacterium tuberculosis , Pruebas de Sensibilidad Microbiana , Antibacterianos/farmacología , Amidas/farmacologíaRESUMEN
The title compound, C15H15F3N2O3S, crystallizes in the monoclinic system, space group I2/a, with Z = 8. As expected, the nine-membered heterobicyclic system is virtually planar and the cyclo-hexyl group adopts a chair conformation. There is structural evidence for intra-molecular N-Sâ¯O chalcogen bonding between the benziso-thia-zolinone S atom and one O atom of the nitro group, approximately aligned along the extension of the covalent N-S bond [N-Sâ¯O = 162.7â (1)°]. In the crystal, the mol-ecules form centrosymmetric dimers through C-Hâ¯O weak hydrogen bonding between a C-H group of the electron-deficient benzene ring and the benzo-thia-zolinone carbonyl O atom with an R 2 2(10) motif. In contrast to the previously described N-acyl 7-nitro-5-(tri-fluoro-meth-yl)benzo[d]iso-thia-zol-3(2H)-ones, the title N-cyclo-hexyl-methyl analogue does not inhibit growth of Mycobacterium aurum and Mycobacterium smegmatis in vitro.