Design, synthesis, biological evaluation, and molecular docking of new benzofuran and indole derivatives as tubulin polymerization inhibitors

Abstract

Microtubules and the mitotic spindle have become an important target for cancer treatment due to their critical role in cell division. In this work, a novel series of benzofuran and indole derivatives were designed and synthesized, to be evaluated as tubulin polymerization inhibitors. 2‐Acetylbenzofuran derivatives 1a,b and 3‐acetylindole 1c were condensed with Wittig reagents 2a–d and Wittig‐Horner reagents 3a–e to afford the respective 2‐ethylidene derivatives 5a–j and 7a–e. Also, iminomethylene triphenylphosphine (2e) reacted with 1a,b to afford benzofuran‐2‐ylethylidene aniline derivatives 6a,b. In addition, compounds 1a,b reacted with trialkylphosphites 4a–c to give 1:1 adduct for which the Oxaphospholo[4,3‐b]benzofuran‐7‐yl)diazene derivatives 8a–f, were assigned. The possible reactions mechanisms were discussed and structural reasoning for the new compounds were based upon spectroscopic data. Their antiproliferative activities against two cell lines namely, HepG2 and MCF7 cells were then evaluated. It was found that the benzofuran compounds 5b, 6a, and 8c exhibited the strongest antiproliferative activities against both cell lines compared to doxorubicin. By studying the mechanism of action, compound 6a showed good inhibition of tubulin polymerization which leads to mitotic spindle formation disruption, cell cycle arrest in the G2/M phase, and apoptosis of HepG2 cells. A conducted docking study confirmed the in vitro results indicating that compound 6a fitted properly at the colchicine binding site of tubulin. Based on these findings, compound 6a can be considered as a promising anticancer candidate that can be subjected for further development as a tubulin polymerization inhibitor for treating liver and breast cell carcinoma.

Anticancer therapeutic potential of benzofuran scaffolds

“…Docking study established the in vitro results conrming that compound 30a was a promising anticancer agent. 51 El-Khouly et al reported the anticancer activity of the benzofuran derivatives 32a-c against four cancer cell lines; HePG2, HeLa, MCF-7 and PC3. The bioassay results conrmed that most of the derivatives had promising inhibitory potency against the dened cell lines with IC 50 values ranging between 8.49-16.72 mM, 6.55-13.14 mM and 4.0-8.99 mM, respectively, when compared with doxorubicin reference drug (4.17-8.87 mM).…”

“…Docking study established the in vitro results confirming that compound 30a was a promising anticancer agent. 51 …”

Synthesis, characterization, docking studies and anti-inflammatory activity of new safe NSAIDs agent based on Ibuprofen phenylalanine derivatives

“…In continuation of synthesis of effective candidates in our laboratory as antimicrobial, antiviral, and anticancer agents [19][20][21][22][23]; we aim to conjugate Ibuprofen with phenyl alanine to be an effective agents as antiinflammatory and analgesic. Our strategy based on preparation of ibuprofen derivatives 1-17 starting from acid chloride 2 that may be expected to have biological activities (Scheme 1).…”

“…To avoid tissue damage the irradiation was automatically stop after 15 s (cut-off = 15 s). Before every trial, the baseline was measured three times, and animals having outranged latency periods were eliminated from the study [22].…”

Insecticidal activity of essential oils from American native plants against Aedes aegypti (Diptera: Culicidae): an introduction to their possible mechanism of action

“…Additionally, scoring function and the prediction of correct binding poses with high accuracy is still challenging; thus, docking scores have little confidence in ranking potential ligands 12 , 13 . However, despite these limitations, structure-based virtual screening, molecular docking simulations, and different computational approaches have been successfully used to identify potential leads for new drug development 14 , 15 . In this sense, the SBVS and other computational tools have been used recently to identify bioactive molecules aiming to inhibit specific molecular targets such as the nicotinic acetylcholine receptor and its use in insecticidal formulation 10 , 16 .…”