Development of 3-methyl/3-(morpholinomethyl)benzofuran derivatives as novel antitumor agents towards non-small cell lung cancer cells

Mohammad M Al-Sanea; Ghada H Al-Ansary; Zainab M Elsayed; Raed M Maklad; Eslam B Elkaeed; Mohamed A Abdelgawad; Syed Nasir Abbas Bukhari; Marwa M Abdel-Aziz; Howayda Suliman; Wagdy M Eldehna

doi:10.1080/14756366.2021.1915302

Development of 3-methyl/3-(morpholinomethyl)benzofuran derivatives as novel antitumor agents towards non-small cell lung cancer cells

J Enzyme Inhib Med Chem. 2021 Dec;36(1):987-999. doi: 10.1080/14756366.2021.1915302.

Authors

Mohammad M Al-Sanea¹, Ghada H Al-Ansary^{2

3}, Zainab M Elsayed⁴, Raed M Maklad^{5

6}, Eslam B Elkaeed^{7

8}, Mohamed A Abdelgawad^{1

9}, Syed Nasir Abbas Bukhari¹, Marwa M Abdel-Aziz¹⁰, Howayda Suliman¹¹, Wagdy M Eldehna⁵

Affiliations

¹ Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia.
² Department of Pharmaceutical Chemistry, Pharmacy Program, Batterejee Medical College, Jeddah, Saudi Arabia.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
⁴ Scientific Research and Innovation Support Unit, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
⁵ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
⁶ Institute of Drug Discovery and Development, Kafrelsheikh University, Kafrelsheikh, Egypt.
⁷ Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Ad Diriyah, Riyadh, Saudi Arabia.
⁸ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo, Egypt.
⁹ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.
¹⁰ The Regional Center for Mycology & Biotechnology, Al-Azhar University, Cairo, Egypt.
¹¹ Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, Egypt.

Abstract

As one of the most lethal malignancies, lung cancer is considered to account for approximately one-fifth of all malignant tumours-related deaths worldwide. This study reports the synthesis and in vitro biological assessment of two sets of 3-methylbenzofurans (4a-d, 6a-c, 8a-c and 11) and 3-(morpholinomethyl)benzofurans (15a-c, 16a-b, 17a-b and 18) as potential anticancer agents towards non-small cell lung carcinoma A549 and NCI-H23 cell lines, with VEGFR-2 inhibitory activity. The target benzofuran-based derivatives efficiently inhibited the growth of both A549 and NCI-H23 cell lines with IC₅₀ spanning in ranges 1.48-47.02 and 0.49-68.9 µM, respectively. The three most active benzofurans (4b, 15a and 16a) were further investigated for their effects on the cell cycle progression and apoptosis in A549 (for 4b) and NCI-H23 (for 15a and 16a) cell lines. Furthermore, benzofurans 4b, 15a and 16a displayed good VEGFR-2 inhibitory activity with IC₅₀ equal 77.97, 132.5 and 45.4 nM, respectively.

Keywords: Benzofuran-2-carbohydrazide; VEGFR-2 inhibitors; anticancer agents; lung cancer.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Benzofurans / chemical synthesis
Benzofurans / chemistry
Benzofurans / pharmacology*
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / metabolism
Carcinoma, Non-Small-Cell Lung / pathology
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Development*
Drug Screening Assays, Antitumor
Humans
Lung Neoplasms / drug therapy*
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Molecular Structure
Structure-Activity Relationship

Substances

Antineoplastic Agents
Benzofurans
benzofuran

Grants and funding

The authors extend their appreciation to the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia for funding this work through the project number "375213500."