Discovery of tetrahydro-β-carboline- and indole-based derivatives as promising phosphodiesterase-4 inhibitors: Synthesis, biological evaluation, and molecular modeling studies

Phosphodiesterase-4 (PDE4) is responsible for the selective degradation of the 3'-cyclic phosphate bonds of cAMP. A collection of twenty-three diverse 1,2,3,4-tertahydro-beta-carboline-and indole-based analogues were synthesized and assessed for their inhibitory activity against human PDE4. The compounds were prepared using straightforward procedures and characterized using H-1-and C-13 NMR, IR, and mass spec-troscopy as well as elemental analysis. Fifteen of the prepared compounds exhibited significant inhibitory activity with IC50 values in the lower micromolar to upper nanomolar ranges. The most active compounds also showed good selectivity for PDE4 over the related enzyme family member, PDE5, with either in-significant or null% inhibition of the latter enzyme. The indole-based compounds, 21b and 21c , showed the most pronounced PDE4 inhibition with IC50 values of 754 and 664 nM, respectively. The PDE4B ac-tive site comprises both hydrophobic and solvent-filled pockets. The Hydrophobic pocket (Q) includes the invariant purine-selective Gln443 which is critical for cAMP. Below this Gln443 lies Phe446 which acts as a hydrophobic P-clamp stabilizing the ligand aromatic ring system. Molecular docking investigation showed preferential anchoring of the active compounds within the PDE4 active site through interactions between the indole nitrogens and the dimethoxy phenyl groups with key residues. Overall, the prepared compounds are novel and simple molecules with good potential for future optimization. Showing sat-isfactory predicted ADME/safety and drug-likeness properties, compound 21c is considered a promising lead for further optimization towards clinical investigation against inflammatory, auto-immune diseases, or certain types of cancer. (C) 2021 Elsevier B.V. All rights reserved.

Automated summary

The synthesized compounds showed potential in inhibiting PDE4 and exhibited good selectivity and specific interactions at the PDE4 active site.