Guanilated Quinolones with Dual Antitubercular and Anti-Inflammatory Activities

Area of Science:

• Medicinal Chemistry
• Infectious Diseases
• Pharmacology

Background:

• Host-directed therapy (HDT) for tuberculosis (TB) aims to shorten treatment by adding adjuvants to standard regimens.
• Current HDT approaches face challenges like increased pill burden, potential nonadherence, drug resistance, and drug-drug interactions.
• Dual-acting molecules offer a promising strategy to simplify TB treatment by combining host targeting and direct antimycobacterial activity.

Purpose of the Study:

• To investigate novel guanilated quinolones as dual inhibitors targeting both Janus Kinase 3 (a host target) and Mycobacterium tuberculosis.
• To identify compounds with the potential to reduce TB treatment duration and pill burden, leading to a simplified therapeutic regimen.

Main Methods:

• Synthesis and evaluation of novel guanilated quinolone derivatives.
• Assay of Janus Kinase 3 (JAK3) inhibitory activity.
• Determination of antitubercular activity against Mycobacterium tuberculosis in vitro using two different growth media.

Main Results:

• Compound 13 demonstrated potent Janus Kinase 3 inhibitory activity, achieving 98% enzyme inhibition at 1 µM concentration.
• Compound 13 exhibited significant antitubercular activity, with efficacy in the range of 0.2–6 µM across different growth media.
• The identified compound acts as a dual inhibitor, engaging both the host target and the pathogen.

Conclusions:

• Novel guanilated quinolones represent a promising class of compounds for developing simplified tuberculosis treatment regimens.
• Compound 13 exemplifies a dual-acting agent with potential for host-directed therapy and direct antimycobacterial effects.
• Further development of such dual inhibitors could significantly impact TB treatment strategies by reducing pill load and potentially overcoming resistance mechanisms.