Design, synthesis, and antitumor efficacy of novel 5-deazaflavin derivatives backed by kinase screening, docking, and ADME studies

Walaa A Bedewy; Mosaad S Mohamed; Ahmed M Abdelhameed; Mohamed A Elsawy; Mohammed Al-Muhur; Noriyuki Ashida; Ashraf N Abdalla; Tamer A Elwaie; Tomohisa Nagamatsu; Hamed I Ali

doi:10.1080/14756366.2023.2220570

Design, synthesis, and antitumor efficacy of novel 5-deazaflavin derivatives backed by kinase screening, docking, and ADME studies

J Enzyme Inhib Med Chem. 2023 Dec;38(1):2220570. doi: 10.1080/14756366.2023.2220570.

Authors

Affiliations

¹ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan University, Helwan, Egypt.
² Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Helwan, Egypt.
³ Leicester Institute of Pharmaceutical Innovation, Leicester School of Pharmacy, De Monfort University, Leicester, UK.
⁴ School of Pharmacy, Queen's University of Belfast, Belfast, UK.
⁵ Doctor Suliman Al Habib Hospital, Riyadh, Saudi Arabia.
⁶ Biology Laboratory, Research and Development Division, Yamasa Co., Chiba, Japan.
⁷ Department of Pharmacology and Toxicology, Pharmacy College, Umm Al-Qura University, Makkah, Saudi Arabia.
⁸ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
⁹ Department of Pharmaceutical Sciences, Irma Lerma Rangel School of Pharmacy, Texas A&M University, College Station, TX, USA.
¹⁰ Faculty of Pharmacological Sciences, Laboratory of Curative Creation Study for Geriatric-diseases Prevention, Sojo University, Kumamoto, Japan.

Abstract

Novel 5-deazaflavins were designed as potential anticancer candidates. Compounds 4j, 4k, 5b, 5i, and 9f demonstrated high cytotoxicity against MCF-7 cell line with IC₅₀ of 0.5-190nM. Compounds 8c and 9g showed preferential activity against Hela cells (IC₅₀: 1.69 and 1.52 μM respectively). However, compound 5d showed notable potency against MCF-7 and Hela cell lines of 0.1 nM and 1.26 μM respectively. Kinase profiling for 4e showed the highest inhibition against a 20 kinase panel. Additionally, ADME prediction studies exhibited that compounds 4j, 5d, 5f, and 9f have drug-likeness criteria to be considered promising antitumor agents deserving of further investigation. SAR study showed that substitutions with 2-benzylidene hydra zino have a better fitting into PTK with enhanced antiproliferative potency. Noteworthy, the incorporation of hydrazino or ethanolamine moieties at position 2 along with small alkyl or phenyl at N-10, respectively revealed an extraordinary potency against MCF-7 cells with IC₅₀ values in the nanomolar range.

Keywords: 5-Deazaflavin; ADME; antitumor; kinase profiling; molecular docking.

MeSH terms

Ethanolamine*
Ethanolamines*
Flavins
HeLa Cells
Humans

Substances

5-deazaflavin
Ethanolamine
Ethanolamines
Flavins

Grants and funding

This research received external funding from the Institute of Scientific Research and Revival of Islamic Heritage, Umm Al-Qura University, Makkah, Saudi Arabia. This work was supported by grant number [43310015] from the Institute of Scientific Research and Revival of Islamic Heritage, Umm Al-Qura University, Makkah, Saudi Arabia, and was also supported in part by the Start-up Fund of Texas A&M Health Sciences Center [to H.I.A. grant number 12150035558].