BTEAC Catalyzed Ultrasonic-Assisted Synthesis of Bromobenzofuran-Oxadiazoles: Unravelling Anti-HepG-2 Cancer Therapeutic Potential through In Vitro and In Silico Studies

Abstract

In this work, BTEAC (benzyl triethylammonium chloride) was employed as a phase transfer catalyst in an improved synthesis (up to 88% yield) of S-alkylated bromobenzofuran-oxadiazole scaffolds BF1-9. These bromobenzofuran-oxadiazole structural hybrids BF1-9 were evaluated in vitro against anti-hepatocellular cancer (HepG2) cell line as well as for their in silico therapeutic potential against six key cancer targets, such as EGFR, PI3K, mTOR, GSK-3β, AKT, and Tubulin polymerization enzymes. Bromobenzofuran structural motifs BF-2, BF-5, and BF-6 displayed the best anti-cancer potential and with the least cell viabilities (12.72 ± 2.23%, 10.41 ± 0.66%, and 13.08 ± 1.08%), respectively, against HepG2 liver cancer cell line, and they also showed excellent molecular docking scores against EGFR, PI3K, mTOR, and Tubulin polymerization enzymes, which are major cancer targets. Bromobenzofuran-oxadiazoles BF-2, BF-5, and BF-6 displayed excellent binding affinities with the active sites of EGFR, PI3K, mTOR, and Tubulin polymerization enzymes in the molecular docking studies as well as in MMGBSA and MM-PBSA studies. The stable bindings of these structural hybrids BF-2, BF-5, and BF-6 with the enzyme targets EGFR and PI3K were further confirmed by molecular dynamic simulations. These investigations revealed that 2,5-dimethoxy-based bromobenzofuran-oxadiazole BF-5 (10.41 ± 0.66% cell viability) exhibited excellent cytotoxic therapeutic efficacy. Moreover, computational studies also suggested that the EGFR, PI3K, mTOR, and Tubulin polymerization enzymes were the probable targets of this BF-5 scaffold. In silico approaches, such as molecular docking, molecular dynamics simulations, and DFT studies, displayed excellent association with the experimental biological data of bromobenzofuran-oxadiazoles BF1-9. Thus, in silico and in vitro results anticipate that the synthesized bromobenzofuran-oxadiazole hybrid BF-5 possesses prominent anti-liver cancer inhibitory effects and can be used as lead for further investigation for anti-HepG2 liver cancer therapy.

In Silico Development of Novel Benzofuran-1,3,4-Oxadiazoles as Lead Inhibitors of M. tuberculosis Polyketide Synthase 13

“…Benzofuran-1,3,4-oxadiazoles BF1–BF16 [ 23 , 45 , 52 ] were evaluated for their anti-Mtb potential using computational approaches. Tuberculosis is a bacterial disease that predominantly affects the lungs and is caused by Mycobacterium tuberculosis [ 53 ].…”

“…The previous work reported on benzofuran-oxadiazoles as anti-microbial agents by our research group and the current comprehensive literature study ( Figure 4 ) [ 17 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ] is the basis of the rationale to discover novel benzofuran-appended oxadiazole structural hybrids as anti-TB drug candidates with the help of different in silico techniques.…”

“…On the other hand, 1,3,4-oxadiazole scaffolds showed a broad spectrum of pharmacological applications; for example, anti-Alzheimer’s [ 36 ], anti-neoplastic [ 37 ], anti-viral [ 38 ], anti-cancer [ 39 ], FAK inhibitors [ 40 ], anti-fungal [ 41 ], anti-inflammatory [ 42 ], anti-bacterial [ 43 ] and anti-tubular activities [ 44 ]. The benzofuran-oxadiazoles also exhibited anti-lung cancer, human tyrosinase inhibitors, anti-HepG-2, anti-hemolytic, and anti-thrombotic activities [ 24 , 45 ]. The different marketed anti-TB drugs are listed in Figure 2 , while potent anti-TB bioactive compounds with oxadiazole and furan cores are depicted in Figure 3 [ 46 , 47 , 48 , 49 , 50 , 51 , 52 ].…”

A Comprehensive Review on Benzofuran Synthesis Featuring Innovative and Catalytic Strategies

“…For example, diabetes, HIV, tuberculosis, epilepsy, and Alzheimer’s disease are some of the most common and widely occurring diseases, against which benzofuran derivatives have been known to play a therapeutic role. In addition, these are effective against a variety of cancers − and are also employed as efficient pain killers. , They also act as efficient enzyme inhibitors, i.e., carbonic anhydrase, , tyrosinase, topoisomerase I, farnesyl transferase, LSD1 (lysine specific demethylase 1), and histamine receptor inibitors . Furthermore, benzofuran derivatives are also widely harnessed in the preparation of different polymers, i.e., polyamides, polyarylates, polybenzimidazoles, and polyesters. , They have also found applications in the synthesis of several dyes including dye-sensitized solar cells and industrial dyes. , …”

Exploring the Synthetic Chemistry of Phenyl-3-(5-aryl-2-furyl)- 2-propen-1-ones as Urease Inhibitors: Mechanistic Approach through Urease Inhibition, Molecular Docking and Structure–Activity Relationship

“…In previously published studies, researchers explored the furan derivatives’ chemotherapeutic potential as bacterial tyrosinase inhibitors, human tyrosinase inhibitors, M. tuberculosis polyketide synthase 13 inhibitors, anti-oxidants, and anticancer agents [ 9 , 24 , 29 , 30 , 31 , 32 , 33 ]. In the present work, structural modifications were carried out to design the synthesis of novel furan chalcone derivatives due to the attractive and promising medicinal and pharmacological profiles of furan and chalcone moieties as cited in the literature [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ].…”