This study target the synthesis of 22 salicylhydrazones derivatives to apply in vitro screening to explore their potential in the search for new anti-TB prototypes drugs.

The minimum inhibitory concentration (MIC) were evaluated against Mycobacterium tuberculosis (Mtb) H₃₇Rv and clinical isolates. Drug combination assay, cytotoxicity assay, ethidium bromide accumulation assay (EtBr) and in silico analysis regarding the absorption, distribution, metabolism, excretion and toxicity (ADMET) and pharmacological properties were also performed.

Three most promising compounds were selected (10, 11 and 18) to proceed with screening tests. Compound 18 presented the lowest MIC value (0.49 μg/mL) against Mtb H₃₇Rv strain, followed by compounds 11 (3.9 μg/mL) and 10 (7.8 μg/mL). All compounds showed activity against drug susceptible and resistant clinical isolates. Cytotoxicity results were promising for all salicylhydrazones, with SI values up to 4,205 for compound 18. The derivative 10 was the only one that demonstrated a non-promising cytotoxicity scenario for a single cell line. All derivatives showed an additive effect (FICI >0.5 to 4.0) in combination with isoniazid, ethambutol and rifampicin.

All salicylhydrazones showed potential in the screening tests performed in this study and compound 18 stood out due to its activity against susceptible and resistant bacilli at low concentrations and low cytotoxicity.