Structure-Guided Drug Design of 6‑Substituted Adenosine Analogues as Potent Inhibitors of Mycobacterium tuberculosis Adenosine Kinase

• Published in: Journal of medicinal chemistry 2019-05, Vol.62 (9), p.4483-4499
• Main Authors: Crespo, Roberto A, Dang, Qun, Zhou, Nian E, Guthrie, Liam M, Snavely, Thomas C, Dong, Wen, Loesch, Kimberly A, Suzuki, Takao, You, Lanying, Wang, Wei, O’Malley, Theresa, Parish, Tanya, Olsen, David B, Sacchettini, James C
• Format: Article
• Language: English
• Subjects: Adenosine - analogs & derivatives; Adenosine - metabolism; Adenosine - pharmacokinetics; Adenosine Kinase - chemistry; Adenosine Kinase - metabolism; Animals; Antitubercular Agents - chemical synthesis; Antitubercular Agents - metabolism; Antitubercular Agents - pharmacokinetics; Catalytic Domain; Drug Design; Female; Mice; Molecular Structure; Mycobacterium tuberculosis - enzymology; Protein Binding; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacokinetics; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b00020

Mycobacterium tuberculosis adenosine kinase (MtbAdoK) is an essential enzyme of Mtb and forms part of the purine salvage pathway within mycobacteria. Evidence suggests that the purine salvage pathway might play a crucial role in Mtb survival and persistence during its latent phase of infection. In these studies, we adopted a structural approach to the discovery, structure-guided design, and synthesis of a series of adenosine analogues that displayed inhibition constants ranging from 5 to 120 nM against the enzyme. Two of these compounds exhibited low micromolar activity against Mtb with half maximal effective inhibitory concentrations of 1.7 and 4.0 μM. Our selectivity and preliminary pharmacokinetic studies showed that the compounds possess a higher degree of specificity against MtbAdoK when compared with the human counterpart and are well tolerated in rodents, respectively. Finally, crystallographic studies showed the molecular basis of inhibition, potency, and selectivity and revealed the presence of a potentially therapeutically relevant cavity unique to the MtbAdoK homodimer.