Phosphorus Dendrimers Functionalized with Anti-Tuberculosis Drugs: Synthesis and Biological Evaluation

Abstract

Tuberculosis remains a major global health challenge, motivating the development of innovative drug delivery strategies. Herein, polyphosphorhydrazone dendrimers were investigated as covalent nanocarriers for anti-tuberculosis drugs. Three dendrimer families, including two novel glycoluril-based architectures, were synthesized and functionalized with several anti-tuberculosis drugs or fragments thereof (isoniazid, pyrazinamide, and thioacetazone), via cleavable acylhydrazone or ester linkages. Isoniazid-functionalized dendrimers bearing acylhydrazone linkages displayed the highest activity against Mycobacterium tuberculosis, with a minimum inhibitory concentration as low as 0.097 μM per dendrimer for the glycoluril-cored generation-zero dendrimer, corresponding to 0.39 μM per isoniazid fragment, an approximately two-fold improvement over free isoniazid. In contrast, ester-functionalized dendrimers were inactive. The most potent dendrimers retained activity against rifampicin-, ethambutol-, and streptomycin-resistant strains, but were inactive against isoniazid-resistant strains and non-tuberculous mycobacteria. Cytotoxicity studies revealed a favorable selectivity index exceeding 100. These results identify low-generation glycoluril-cored polyphosphorhydrazone dendrimers as promising platforms for anti-tuberculosis drug delivery.