Journal Article

Development of Novel Isatin-Tethered Quinolines as Anti-Tubercular Agents against Multi and Extensively Drug-Resistant Mycobacterium tuberculosis

Said, Mohamed A., Majrashi, Taghreed A., Abdel-Aziz, Marwa M., Al-Warhi, Tarfah, Abdelrahman, Mohamed A., Almahli, Hadia, Eldehna, Wagdy M.

2022

Overview

We describe the design and synthesis of two isatin-tethered quinolines series (Q6a–h and Q8a–h), in connection with our research interest in developing novel isatin-bearing anti-tubercular candidates. In a previous study, a series of small molecules bearing a quinoline-3-carbohydrazone moiety was developed as anti-tubercular agents, and compound IV disclosed the highest potency with MIC value equal to 6.24 µg/mL. In the current work, we adopted the bioisosteric replacement approach to replace the 3,4,5-trimethoxy-benzylidene moiety in the lead compound IV with the isatin motif, a privileged scaffold in the TB drug discovery, to furnish the first series of target molecules Q6a–h. Thereafter, the isatin motif was N-substituted with either a methyl or benzyl group to furnish the second series Q8a–h. All of the designed quinoilne-isatin conjugates Q6a–h and Q8a–h were synthesized and then biologically assessed for anti-tubercular actions towards drug-susceptible, MDR, and XDR strains. Superiorly, the N-benzyl-bearing compound Q8b possessed the best activities against the examined M. tuberculosis strains with MICs equal 0.06, 0.24, and 1.95 µg/mL, respectively.

• Publisher: MDPI AG,MDPI
• Subject: anti-mycobacterial activity / Antitubercular Agents - pharmacology / Drug Design / Drug resistance / hydrazone / Isatin - pharmacology / Microbial Sensitivity Tests / Mycobacterium resistance / Mycobacterium tuberculosis / Quinolines - pharmacology / quinolone / Structure-Activity Relationship / Tuberculosis