Gadekar Pradip K, Roychowdhury Abhijit, Kharkar Prashant S, Khedkar Vijay M, Arkile Manisha, Manek Hardik, Sarkar Dhiman, Sharma Rajiv, Vijayakumar V, Sarveswari S
Department of Medicinal Chemistry, Piramal Enterprises Ltd., 1, Nirlon Complex, Goregaon (East), Mumbai, 400063, India.
Department of Pharmaceutical Chemistry, SPP School of Pharmacy and Technology Management, SVKM's NMIMS, V. L. Mehta Road, Vile Parle (West), Mumbai, 400 056, India.
Eur J Med Chem. 2016 Oct 21;122:475-487. doi: 10.1016/j.ejmech.2016.07.001. Epub 2016 Jul 7.
The design, synthesis and antimicrobial evaluation of a novel series of azaspiro analogues of linezolid (1) have been described. Linezolid comprises of a morpholine ring which is known for its metabolism-related liabilities. Therefore, the key modification made in the linezolid structure was the replacement of morpholine moiety with its bioisostere, 2-oxa-6-azaspiro[3.3]heptane. Furthermore, the replacement of N-acetyl terminal of 1 with various aromatic or aliphatic functionalities was carried out. The title compounds were evaluated against a panel of Gram-positive and Gram-negative bacteria and Mycobacterium tuberculosis. Subsequent structure-activity relationship (SAR) studies identified several compounds with mixed antibacterial and antitubercular profiles. Compound 22 (IC50 0.72, 0.51, 0.88, 0.49 μg/mL for Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis, respectively) exhibited similar antibacterial profile as 1. The N-acetyl derivative 18 was similar to 1 in antitubercular profile. Thus, the present study successfully demonstrated the use of azaspiro substructure in the medicinal chemistry of antibacterial and antitubercular agents.
已描述了一系列新型利奈唑胺（1）氮杂螺类似物的设计、合成及抗菌评估。利奈唑胺含有一个因其与代谢相关的缺陷而闻名的吗啉环。因此，在利奈唑胺结构中进行的关键修饰是用其生物电子等排体2-氧杂-6-氮杂螺[3.3]庚烷取代吗啉部分。此外，还进行了用各种芳香或脂肪族官能团取代1的N-乙酰基末端的操作。对标题化合物针对一组革兰氏阳性菌、革兰氏阴性菌和结核分枝杆菌进行了评估。随后的构效关系（SAR）研究确定了几种具有混合抗菌和抗结核活性的化合物。化合物22（对大肠杆菌、铜绿假单胞菌、金黄色葡萄球菌、枯草芽孢杆菌的IC50分别为0.72、0.51、0.88、0.49μg/mL）表现出与1相似的抗菌活性。N-乙酰基衍生物18在抗结核活性方面与1相似。因此，本研究成功证明了氮杂螺亚结构在抗菌和抗结核药物的药物化学中的应用。
