Synthesis and Tuberculostatic Activity Evaluation of Novel Benzazoles with Alkyl, Cycloalkyl or Pyridine Moiety

Abstract

Compounds possessing benzimidazole system exhibit significant antituberculous activity. In order to examine how structure modifications affect tuberculostatic activity, a series of benzazole derivatives were synthesized and screened for their antitubercular activity. The compounds 1–20 were obtained by the reaction between o-diamine, o-aminophenol, or o-aminothiophenol with carboxylic acids or thioamides. The newly synthesized compounds were characterized by IR, 1H-NMR, 13C-NMR spectra, and elemental analysis. Synthesized benzazoles were evaluated for their tuberculostatic activity toward Mycobacterium tuberculosis strains. Quantum chemical calculations were performed to study the molecular geometry and the electronic structure of benzimidazoles GK-151B, 4, 6, and benzoxazole 11, using the Gaussian 03W software (Gaussian, Inc., Wallingford, CT, USA). Three-dimensional structure of benzimidazoles 1–3, MC-9, and GK-151B was determined by ab initio calculation using Gamess-US software. The activity of the received benzimidazoles was moderate or good. All of the benzoxazoles and benzothiazoles demonstrated much lower activity. Benzoxazoles were less active by about 50 times, and benzothiazole by 100 times than the benzimidazole analogs. Quantum chemical calculations showed differences in the distribution of electrostatic potential in the benzazole system of benzimidazoles and benzoxazoles. Three-dimensional structure calculations revealed how the parity of the alkyl substituent at the C2 position impacts the activity. Benzimidazole system is essential for the antituberculosis activity that is associated with the presence of the imine nitrogen atom in N-1 position. Its replacement by an oxygen or sulfur atom results in a decrease of the activity. The parity of the alkyl substituent at the C-2 position also modifies the activity.

Nickel-catalyzed tandem isomerization/anti-Markovnikov hydroarylation of unactivated internal alkenes with heteroarenes

“…We noted that 6ak is a core structure of an antituberculosis agent. 19 The catalytic system also worked well with terminal alkenes, resulting in linear products ( 6al and 6am ) in 72–77% yields with good regioselectivity ( L : B = ≥92 : 8).…”

Design, Synthesis, and Antifungal Activities of Hymexazol Glycosides Based on a Biomimetic Strategy

“…Because glycoside 5 has a larger dipole moment (8.8680 D) and partition coefficient (−0.97), it may be poorly absorbed by cells and show lower activity. 39 The in vitro antifungal activity proved that glycosylation of HYM could enhance its antifungal activity, but not all sugar units and glycosidic bonds were acceptable. Combined with the structure−activity analysis obtained by quantum chemistry, we found that the glycosylation site of HYM must be located on the hydroxyl group.…”

“…Glycoside 15 has a smaller dipole moment (8.2293 D) and partition coefficient (−1.42) than glycoside 5 . Because glycoside 5 has a larger dipole moment (8.8680 D) and partition coefficient (−0.97), it may be poorly absorbed by cells and show lower activity …”

Relationship between the Crystal Structure and Tuberculostatic Activity of Some 2-Amidinothiosemicarbazone Derivatives of Pyridine

“…The study described below is a continuation of our previous studies on amidrazone derivatives exhibiting high anti-tuberculosis activity [ 7 , 8 , 9 , 10 , 11 , 12 ]. The previous studies allowed us to formulate a hypothesis that the planarity of these molecules being isoniazid analogues (INH) is a significant prerequisite for their tuberculostatic activity.…”