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

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.

Graphical abstract

Keywords:

• 5-Deazaflavin
• antitumor
• molecular docking
• kinase profiling
• ADME

Author contributions

Participated in research design: Hamed I. Ali and Mosaad S. Mohamed. Conducted experiments: Walaa A. Bedewy, Ahmed M. Abdelhameed, Noriyuki Ashida, Mohamed A. Elsawy, Mohammed Al-Muhur. Performed data analysis: Hamed I. Ali, Tamer A. Elwaie, Ashraf N Abdalla, Noriyuki Ashida, Tomohisa Nagamatsu. Wrote or contributed to the writing of the manuscript: Hamed I.Ali, Walaa A. Bedewy, Tamer A. Elwaie, Ahmed M. Abdelhameed, Ashraf N Abdalla

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

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].