Quinolizidine derivatives with antitubercular activity

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Pharmacology

Background:

• Tuberculosis remains a significant global health challenge, necessitating the development of novel therapeutic agents.
• The quinolizidine scaffold is a privileged structure in medicinal chemistry, with potential for diverse biological activities.

Purpose of the Study:

• To synthesize novel quinolizidine derivatives incorporating lupine and diarylmethane moieties.
• To evaluate the in vitro antitubercular activity of the synthesized compounds against Mycobacterium tuberculosis H37RV.

Main Methods:

• Synthesis of lupinyldiarylcarbinols via Grignard reaction of lupinylmagnesium chloride with aromatic ketones.
• Dehydration of carbinols to form unsaturated lupinylidenediarylmethanes.
• Reduction of unsaturated compounds to yield lupinyldiarylmethanes.
• Direct condensation of lupinine with fluorene to obtain 9-epi-lupinylfluorene.
• Antitubercular activity screening using Minimum Inhibitory Concentration (MIC) assays.

Main Results:

• Several novel quinolizidine derivatives were successfully synthesized.
• Nine compounds exhibited good antitubercular activity, with MIC values below 8 micrograms/ml.
• One lupinylidene derivative (compound 13) displayed potent activity, with an MIC between 0.1 and 0.5 micrograms/ml.

Conclusions:

• The synthesized quinolizidine derivatives represent a promising class of compounds for tuberculosis treatment.
• Further investigation into the structure-activity relationship and mechanism of action is warranted.
• Compound 13 is a lead candidate for further preclinical development as an antitubercular agent.