1,2,3-Triazole Tethered Hybrid Capsaicinoids as Antiproliferative Agents Active against Lung Cancer Cells (A549)

Abstract

A series of novel 1,2,3-triazole derivatives of capsaicin and its structural isomer (new natural product hybrid capsaicinoid) were synthesized by exploiting one-/two-point modification of capsaicin without altering the amide linkage (neck). The newly synthesized compounds were screened for their antiproliferative activity against an NCI panel of 60 cancer cell lines at a single dose of 10 μM. Most of the compounds have demonstrated reduced growth between 55 and 95%, whereas capsaicin ( 10 ) has shown reduced growth between 0 and 24%. Compounds showing more than 50% growth inhibition were further evaluated for the IC 50 value. Among the cell lines tested, lung cancer cell lines (A549, NCI-H460) were found to be more susceptible toward most of the synthesized compounds. Compounds 14g and 14j demonstrated good antiproliferative activity in NCI-H460 with IC 50 values of 6.65 and 5.55 μM, respectively, while compounds 18b , 18c , 18f , and 18m demonstrated potential antiproliferative activity in A549 cell lines with IC 50 values ranging between 2.9 and 10.5 μM. Among the compounds, compound 18f was found to demonstrate the best activity with an IC 50 value of 2.91 μM against A549. Furthermore, 18f induces cell cycle arrest at the S-phase and disrupts the mitochondrial membrane potential, reducing cell migration potential by inducing cellular apoptosis and higher ROS generation along with a decrease in mitochondrial membrane potential in addition to surface and nuclear morphological alterations such as a reduction in the number and shrinkage of cells coupled with nuclear blabbing indicating the sign of apoptosis of A549 non-small cell lung cancer cell lines. Compound 18f has emerged as a lead molecule and may serve as a template for further discovery of capsaicinoid scaffolds.

Capsaicin derivatives: Synthesis and biological activity

“…As a crucial pharmacophore processing a broad of pharmacological activities, 1,2,3-triazole was integrated with capsaicin in this paper. Arif et al (Khan et al, 2022) synthesized a series of derivatives via onepoint modification and two-point modification and screened compounds 59a-59f form investigation against 60 cell lines. Among these derivatives, 59f was viewed as an anticancer agent against lung cancer due to it fantastic performance of IC 50 value (2.92 μM) (Table 6), via triggering the elevation of ROS levels, promoting A549 cells apoptosis, influencing cell cycle, and inhibiting migration of cells.…”

Synthesis of New Imidazo[1,2‐a]pyridine Triazole Hybrid Molecules as Potential Apoptotic Antitumor Agents

“…1,2,3‐Triazole isomeric forms of triazoles can exhibit a wide variety of pharmacological activities as they can interact with different biological targets via hydrogen bonds, hydrophobic interactions and Van der Waals forces. Compared with other heterocyclic compounds, they are stated to be quite stable against metabolic degradation [18,19] . They exhibit many different therapeutic properties such as antimicrobial, [20] antibacterial, [21] antiviral, [22] anticholinesterase, [23] antioxidants, [24] antidiabetic, [25] anticancer, [26] and antiinflammatory [27] .…”

“…Compared with other heterocyclic compounds, they are stated to be quite stable against metabolic degradation. [18,19] They exhibit many different therapeutic properties such as antimicrobial, [20] antibacterial, [21] antiviral, [22] anticholinesterase, [23] antioxidants, [24] antidiabetic, [25] anticancer, [26] and antiinflammatory. [27] In addition, 1,2,3-triazole hybrid pharmacophores are highly effective against drugsensitive, drug-resistant cancer cell lines [28][29][30] and they show anticancer effects through different pathways including inhibition of enzymes, PARP-1, tubulin, carbonic anhydrases (CA's), aromatase, indoleamine 2,3-dioxygenase 1 (IDO1), epidermal growth factor receptor (EGFR).…”

Small Peptide Conjugates of Benzothiazole‐2‐Carboxylic Acids Targeting DprE1 Against Tuberculosis

“…TCA1 analogues bearing benzothiazole war heads were proved to be noncovalent inhibitors of DprE1. [2,[24][25][26][27][28] Furthermore, in the last few decades, several peptides have been identified as promising drug candidates for M.tb (Figure 3). They have demonstrated potential anti-tubercular activities alone as well as in combination with pre-existing drugs.…”

“…Moreover, most of the newly explored non‐covalent DprE1 inhibitors contain the benzothiazole nucleus, which has already been established as a potent pharmacophore well‐known for other important pharmacological properties including anti‐cancer, anti‐malarial, anti‐diabetic, anti‐microbial, anti‐convulsant, anti‐HIV, and anti‐leishmanial activities. TCA1 analogues bearing benzothiazole war heads were proved to be non‐covalent inhibitors of DprE1 [2,24–28] …”