Bangalore Pavan Kumar, Pedapati Ravi Kumar, Pranathi Abburi Naga, Batchu Uma Rajeswari, Misra Sunil, Estharala Madhurekha, Sriram Dharmarajan, Kantevari Srinivas
Fluoro and Agrochemicals Division, CSIR- Indian Institute of Chemical Technology, Hyderabad, Telangana, 500007, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, 201002, India.
Mol Divers. 2023 Apr;27(2):811-836. doi: 10.1007/s11030-022-10456-y. Epub 2022 May 24.
Lichen secondary metabolites are well explored medicinal agents with diverse pharmacological properties. One of the important antibiotic lichen secondary metabolites is usnic acid. Its diverse medicinal profiles prompted us to explore it as a potential antitubercular molecule. Towards this direction, continuing our efforts on the discovery and development of new analogs with potent antitubercular properties we designed, synthesized, and evaluated a set of 37 usnic acid enaminone-coupled aryl-n-hexanamides (3-39). The study yielded a 3,4-dimethoxyphenyl compound (13, 5.3 µM) as the most active anti-TB molecule. The docking studies were performed on 7 different enzymes to better understand the binding modes, where it was observed that compound 13 bound strongly with glucose dehydrogenase (Gscore: - 9.03). Further antibacterial investigations revealed compound 2 with potent inhibition on Salmonella typhi and Bacillus subtilis (MIC 3 µM) and MIC values of 7 and 14 µM on Streptococcus mutans and Escherichia coli respectively. Compound 19 (3-F-5-CF-phenyl) displayed encouraging antibacterial profiles against E. coli, S. typhi and S. mutans with MIC values of 10 µM respectively. Interestingly, compound 20 (2,6-difluorophenyl) also displayed good antibacterial activity against E. coli with an MIC value of 6 µM. These encouraging pharmacological results will help for better designing and developing usnic acid-based semi-synthetic derivatives as potential antimicrobial agents. A set of 37 new usnic acid enaminone-coupled aryl-n-hexanamides were synthesized and evaluated as potential antimicrobial agents. Compound 13 was identified as the most active antitubercular molecule. 13 was further docked against 7 different enzymes of tuberculosis. The molecule displayed maximum binding energy with the enzyme Glucose dehydrogenase (Gscore: - 9.03), indicating that these hexanamides possibly act by inhibiting the glucose metabolic pathway of the bacterium. Surprisingly, the intermediate hexanoic acid 2 was identified as potent antibacterial agent, acting on both gram-positive and gram-negative bacterial strains (3-14 μM). The active compounds may be subjected to structural iterations to develop further leads.
地衣次生代谢产物是具有多种药理特性的药用剂，已得到充分研究。重要的抗生素地衣次生代谢产物之一是松萝酸。其多样的药用特性促使我们将其作为一种潜在的抗结核分子进行探索。朝着这个方向，我们继续努力发现和开发具有强效抗结核特性的新类似物，设计、合成并评估了一组37种松萝酸烯胺酮偶联的芳基正己酰胺（3 - 39）。该研究得到了一种3,4 - 二甲氧基苯基化合物（13，5.3 μM），它是活性最强的抗结核分子。对7种不同的酶进行了对接研究，以更好地了解其结合模式，结果发现化合物13与葡萄糖脱氢酶结合紧密（Gscore： - 9.03）。进一步的抗菌研究表明，化合物2对伤寒沙门氏菌和枯草芽孢杆菌有强效抑制作用（MIC为3 μM），对变形链球菌和大肠杆菌的MIC值分别为7 μM和14 μM。化合物19（3 - F - 5 - CF - 苯基）对大肠杆菌、伤寒沙门氏菌和变形链球菌显示出令人鼓舞的抗菌特性，MIC值均为10 μM。有趣的是，化合物20（2,6 - 二氟苯基）对大肠杆菌也显示出良好的抗菌活性，MIC值为6 μM。这些令人鼓舞的药理结果将有助于更好地设计和开发基于松萝酸的半合成衍生物作为潜在的抗菌剂。合成并评估了一组37种新的松萝酸烯胺酮偶联的芳基正己酰胺作为潜在的抗菌剂。化合物13被确定为活性最强的抗结核分子。对13进一步针对7种不同的结核酶进行对接。该分子与葡萄糖脱氢酶显示出最大结合能（Gscore： - 9.03），表明这些己酰胺可能通过抑制细菌的葡萄糖代谢途径起作用。令人惊讶的是，中间产物己酸2被确定为强效抗菌剂，对革兰氏阳性和革兰氏阴性细菌菌株均有作用（3 - 14 μM）。活性化合物可进行结构迭代以开发更多先导化合物。
