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

Molecules. 2018 Apr 23;23(4):985. doi: 10.3390/molecules23040985.

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 120 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 13, 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.

Keywords: SAR-study; benzazole; pyridine; quantum chemical calculations; synthesis; tuberculostatic activity.

MeSH terms

  • Antitubercular Agents / chemical synthesis*
  • Antitubercular Agents / chemistry*
  • Antitubercular Agents / pharmacology
  • Benzimidazoles / chemistry
  • Benzothiazoles / chemistry
  • Benzoxazoles / chemistry*
  • Molecular Structure
  • Mycobacterium tuberculosis / drug effects
  • Pyridines / chemistry*
  • Structure-Activity Relationship

Substances

  • Antitubercular Agents
  • Benzimidazoles
  • Benzothiazoles
  • Benzoxazoles
  • Pyridines
  • benzimidazole
  • benzothiazole
  • pyridine