Discovery of Small Molecule COX-1 and Akt Inhibitors as Anti-NSCLC Agents Endowed with Anti-Inflammatory Action

Abstract

Targeted therapies have come into prominence in the ongoing battle against non-small cell lung cancer (NSCLC) because of the shortcomings of traditional chemotherapy. In this context, indole-based small molecules, which were synthesized efficiently, were subjected to an in vitro colorimetric assay to evaluate their cyclooxygenase (COX) inhibitory profiles. Compounds 3b and 4a were found to be the most selective COX-1 inhibitors in this series with IC50 values of 8.90 µM and 10.00 µM, respectively. In vitro and in vivo assays were performed to evaluate their anti-NSCLC and anti-inflammatory action, respectively. 2-(1H-Indol-3-yl)-N′-(4-morpholinobenzylidene)acetohydrazide (3b) showed selective cytotoxic activity against A549 human lung adenocarcinoma cells through apoptosis induction and Akt inhibition. The in vivo experimental data revealed that compound 3b decreased the serum myeloperoxidase and nitric oxide levels, pointing out its anti-inflammatory action. Moreover, compound 3b diminished the serum aminotransferase (particularly aspartate aminotransferase) levels. Based on the in vitro and in vivo experimental data, compound 3b stands out as a lead anti-NSCLC agent endowed with in vivo anti-inflammatory action, acting as a dual COX-1 and Akt inhibitor.

Anti-proliferative activity of nitroquinolone fused acylhydrazones as non-small cell human lung cancer agents

“…27 The presence of hydrazide-hydrazone linkers have also shown anti-cancer activity against non-small cell lung cancer cell lines (NSCLC's). 28–30…”

“…27 The presence of hydrazide-hydrazone linkers have also shown anti-cancer activity against non-small cell lung cancer cell lines (NSCLC's). [28][29][30] Quinolines are well known for their antimalarial nature and recently their uses have extended further into the disciplines of anti-diabetic agents, 31 anti-cancer therapeutics, 32,33 neurodegenerative diseases 34 etc. The quinoline base exhibits strong binding with various apoptotic proteins, thereby making the heterocycle a good starting point for anti-cancer drug design strategies.…”

Design, Synthesis, and Evaluation of a New Series of Hydrazones as Small-Molecule Akt Inhibitors for NSCLC Therapy

“…14−18 Hydrazones have been reported to exert striking antitumor action via induction of apoptosis, cell cycle arrest, inhibition of angiogenesis, and a plethora of cancer-related biological targets (e.g., Akt). 19 Benzoxazoles are privileged building blocks for the synthesis of biologically active ligands targeting a plethora of crucial targets/pathways due to their unique features allowing them to effectively bind to diverse biological targets with distinct affinities. 27−31 Several studies have revealed that benzoxazoles exert marked cytotoxic activity against a variety of cancer cell lines through diverse mechanisms including induction of apoptosis, inhibition of Akt phosphorylation, and so on.…”

“…The publications related to hydrazones − and benzoxazoles − exerting pronounced anticancer activity through inhibition of target enzymes involved in the pathogenesis of lung cancer motivated us to design novel anti-NSCLC agents by means of the molecular hybridization of the benzoxazole core with the hydrazide group, which was conjugated with the benzylidene moiety substituted at the para position with dialkylamino groups (dimethylamino, diethylamino), nitrogen-containing electron-withdrawing groups (nitro substituent), five- (pyrrolidine) or six-membered heterocyclic motifs (piperidine, morpholine and piperazine), heteroaromatic rings (imidazole, triazole) based on our previous work (Figure ), and the structure–activity relationships of existing Akt inhibitors together with the bioisosteric replacement. In this context, the designed compounds were synthesized readily and assessed for their cytotoxic properties on human lung adenocarcinoma (A549) and mouse embryonic fibroblast (L929) cells.…”

“…Hydrazides-hydrazones are frequently occurring eligible motifs in druglike small molecules due to their distinctive characteristics and several pharmaceutical applications for the treatment of many diseases, particularly severe bacterial infections, cancer, and inflammation. − Hydrazones have been reported to exert striking antitumor action via induction of apoptosis, cell cycle arrest, inhibition of angiogenesis, and a plethora of cancer-related biological targets (e.g., Akt). − …”