Spectrofluorimetric and Computational Investigation of New Phthalimide Derivatives towards Human Neutrophil Elastase Inhibition and Antiproliferative Activity

Abstract

Herein, nine phthalimide-based thiazoles (4a–4i) were synthesized and investigated as new human neutrophil elastase (HNE) inhibitors using spectrofluorimetric and computational methods. The most active compounds containing 4-trifluoromethyl (4c), 4-naphthyl (4e) and 2,4,6-trichloro (4h) substituents in the phenyl ring exhibited high HNE inhibitory activity with IC50 values of 12.98–16.62 µM. Additionally, compound 4c exhibited mixed mechanism of action. Computational investigation provided a consistent picture of the ligand-receptor pattern of inter-actions, common for the whole considered group of compounds. Moreover, compounds 4b, 4c, 4d and 4f showed high antiproliferative activity against human cancer cells lines MV4-11, and A549 with IC50 values of 8.21 to 25.57 µM. Additionally, compound 4g showed high activity against MDA-MB-231 and UMUC-3 with IC50 values of 9.66 and 19.81 µM, respectively. Spectrophotometric analysis showed that the most active compound 4c demonstrated high stability under physiological conditions.

Phthalimides Represent a Promising Scaffold for Multi‐Targeted Anticancer Agents

“…Nowadays, different researchers’ groups are working in two directions; first one is to design target‐specific drugs and the second one is multi‐targeted drug design as both have their own advantages and disadvantages. As reported (wide infra), phthalimide scaffolds have an affinity towards various cancer‐causing targets and factors such as VEGFR, EGFR, PDGFR, TNF‐α, caspase 3/7/9, PROTACs, DNA gyrase B, tryptase, and HDACs [27–33,38–52,56,60–67] that gives an opportunity for researchers to develop more promising multi‐targeted efficient drug of choices to treat the different cancers through drugs acting by multiple mechanisms. The De‐novo and fragment‐based drug design approaches will play a pivotal role while designing multi‐targeted anticancer agents.…”

“…Scientists and medicinal chemists already defined the advantageous and need of polypharmacology or multi‐targetedapproach to treat diseases like cancer, parkinson's and alzheimer disease [81,82] . In our preceding discussion, we described the nature and complementary shape and characteristics of phthalimide derivatives and their affinity towards different cancer receptors responsible for stimulating multiple‐mechanisms in cancer inhibition [27–33,38–52,56,60–67] . The US FDA already approved phthalimide scaffolds containing drugs (thalidomide, lenalidomide, and pomalidomide) with anticancer activity via multiple mechanisms.…”

“…Compound 11 has shown 16 fold amplified potency than control against A549 cells by caspase 3/7 activation assay. Again, compound 10 proved its potency by showing maximum inhibition by EGFR inhibition assay while, elastase assay showed compound 10 and 11 both are potent with IC 50 values 32.1 and 32.9 μM, respectively [31] …”