Department of Organic Chemistry, Medical University of Gdańsk, 107 Gen. Hallera Ave., 80416 Gdańsk, Poland.
Department of Microbiology, Institute of Tuberculosis and Pulmonary Diseases, 26 Płocka Str., 01138 Warsaw, Poland.
Molecules. 2018 Apr 23;23(4):985. doi: 10.3390/molecules23040985.
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 ⁻ were obtained by the reaction between -diamine, -aminophenol, or -aminothiophenol with carboxylic acids or thioamides. The newly synthesized compounds were characterized by IR, ¹H-NMR, C-NMR spectra, and elemental analysis. Synthesized benzazoles were evaluated for their tuberculostatic activity toward strains. Quantum chemical calculations were performed to study the molecular geometry and the electronic structure of benzimidazoles GK-151B, , , and benzoxazole , using the Gaussian 03W software (Gaussian, Inc., Wallingford, CT, USA). Three-dimensional structure of benzimidazoles ⁻, 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.
具有苯并咪唑系统的化合物表现出显著的抗结核活性。为了研究结构修饰如何影响结核抑制活性，我们合成了一系列苯并唑衍生物并对其抗结核活性进行了筛选。这些化合物是通过 -二胺、-氨基酚或 -氨基噻酚与羧酸或硫代酰胺反应得到的。新合成的化合物通过 IR、¹H-NMR、C-NMR 光谱和元素分析进行了表征。合成的苯并唑类化合物对 菌株的结核抑制活性进行了评估。使用 Gaussian 03W 软件（Gaussian，Inc.，Wallingford，CT，USA）对苯并咪唑 GK-151B、、、和苯并恶唑的分子几何形状和电子结构进行了量子化学计算。使用 Gamess-US 软件通过从头算计算确定了苯并咪唑 ⁻、MC-9 和 GK-151B 的三维结构。所得到的苯并咪唑的活性为中等或良好。所有的苯并恶唑和苯并噻唑的活性都低得多。苯并恶唑的活性比苯并咪唑类似物低约 50 倍，苯并噻唑的活性比苯并咪唑类似物低 100 倍。量子化学计算表明，苯并唑系统中静电势的分布存在差异，苯并咪唑和苯并恶唑的分布存在差异。三维结构计算揭示了 C2 位烷基取代基的奇偶性如何影响活性。苯并咪唑系统对于抗结核活性是必不可少的，这与 N-1 位的亚胺氮原子的存在有关。用氧或硫原子取代它会导致活性降低。C-2 位烷基取代基的奇偶性也会改变活性。
