14-a

The rise of drug-resistant tuberculosis (TB) has created an urgent need to discover and develop new anti-mycobacterial agents. Herein, we report the synthesis and evaluation of a library of 1,3-diaryl substituted pyrazole-based imidazo[1,2-a]pyridine carboxamides as promising anti-TB agents. In preliminary screening, 10 out of 26 compounds displayed potent in vitro inhibition against Mtb H37Rv with a MIC value of 0.03 μg/mL, which is 17-fold more potent than the first-line TB drug streptomycin, 33-fold more potent than ethambutol, and equipotent with isoniazid and rifampicin. Encouragingly, most of these compounds exhibited a selectivity index (SI) >3333.3 and CC₅₀ values >100 μg/mL against Vero cells, indicating they are over 3000 times more toxic to M. tuberculosis than to mammalian cells and demonstrate absence of cytotoxicity at concentrations effective against TB (MIC = 0.03 μg/mL). Among them, 12a, 14a, and 14d demonstrated remarkable activity against drug-resistant strains of Mtb with an MIC of 0.03 μM. Time-kill kinetic studies revealed that 12a, 14a, and 14d exhibited bacteriostatic properties. Furthermore, 12a, 14a, and 14d demonstrated synergistic effects with the FDA-approved anti-TB drugs rifampicin (ƩFIC 0.093), ethambutol (ƩFIC 0.061), and moxifloxacin (ƩFIC 0.154-0.281), exhibiting bactericidal time-kill properties in combination with these drugs. Additionally, 12a, 14a, and 14d exhibited acceptable metabolic stability (CL_int 11.49-14.62 μL/min/mg microsomal protein), indicating effective drug levels and bioavailability. Also, 12a, 14a, and 14d showed stable interactions with QcrB in docking studies. These findings highlight 12a, 14a, and 14d as potential candidates for in vivo evaluation and further development as novel anti-tubercular drugs.

Phosphodiesterase 5 (PDE5) inhibitors have been suggested as new treatments for Alzheimer's disease (AD) and other conditions such as cancer and cardiovascular diseases. Utilizing the widespread presence of the indole moiety in biomolecules and drugs, previously synthesized quinoline and naphthyridine compounds were modified into novel indole-containing PDE5 inhibitors. Replacing the amine with an amide group led to identifying a potent analogue, compound 14a, with an IC₅₀ of 16.11 nM. Molecular docking simulations further highlight the significance of the amide group in drug-target interactions. A cytotoxicity test and a parallel artificial membrane permeability assay validated the compound's potential as a lead for further drug development. Compound 14a was shown to be safe and blood-brain barrier permeable. The discovery of these indole-containing PDE5 inhibitors provides new perspectives for developing PDE5 therapeutics.