Design, synthesis, molecular modeling, in vitro and in vivo biological evaluation of potent anthranilamide derivatives as dual P-glycoprotein and CYP3A4 inhibitors

Ahmed M Said; Yara E Mansour; Radwa R Soliman; Ridwan Islam; Samar S Fatahala

doi:10.1016/j.ejmech.2024.116492

Design, synthesis, molecular modeling, in vitro and in vivo biological evaluation of potent anthranilamide derivatives as dual P-glycoprotein and CYP3A4 inhibitors

Eur J Med Chem. 2024 Jul 5:273:116492. doi: 10.1016/j.ejmech.2024.116492. Epub 2024 May 11.

Authors

Ahmed M Said¹, Yara E Mansour², Radwa R Soliman³, Ridwan Islam⁴, Samar S Fatahala⁵

Affiliations

¹ Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, BCC, Omaha, NE, 68198, USA; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Ein-Helwan, Helwan, Cairo, 11795, Egypt; Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY, 14260, USA. Electronic address: [email protected].
² Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Ein-Helwan, Helwan, Cairo, 11795, Egypt.
³ Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, 14260, USA.
⁴ Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, BCC, Omaha, NE, 68198, USA.
⁵ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Ein-Helwan, Helwan, Cairo, 11795, Egypt. Electronic address: [email protected].

PMID: 38762918
DOI: 10.1016/j.ejmech.2024.116492

Abstract

Paclitaxel (PTX) is considered the blockbuster chemotherapy treatment for cancer. Paclitaxel's (PTX) oral administration has proven to be extremely difficult, mostly because of its susceptibility to intestinal P-glycoprotein (P-gp) and cytochrome P450 (CYP3A4). The concurrent local inhibition of intestinal P-gp and CYP3A4 is a promising approach to improve the oral bioavailability of paclitaxel while avoiding potential unfavorable side effects of their systemic inhibition. Herein, we report the rational design and evaluation of novel dual potent inhibitors of P-gp and CYP3A4 using an anthranilamide derivative tariquidar as a starting point for their structural optimizations. Compound 14f, bearing N-imidazolylbenzyl side chain, was found to have potent and selective P-gp (EC₅₀ = 28 nM) and CYP3A4 (IC₅₀ = 223 nM) inhibitory activities with low absorption potential (P_app (A-to-B) <0.06). In vivo, inhibitor 14f improved the oral absorption of paclitaxel by 6 times in mice and by 30 times in rats as compared to vehicle, while 14f itself remained poorly absorbed. Compound 14f, possessing dual P-gp and CYP3A4 inhibitory activities, offered additional enhancement in paclitaxel oral absorption compared to tariquidar in mice. Evaluating the CYP effect of 14f on oral absorption of paclitaxel requires considering the variations in CYP expression between animal species. This study provides further medicinal chemistry advice on strategies for resolving concerns with the oral administration of chemotherapeutic agents.

Keywords: Anthranilamide; CYP3A4; Oral bioavailability; P-glycoprotein; Paclitaxel; Tariquidar.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1* / antagonists & inhibitors
ATP Binding Cassette Transporter, Subfamily B, Member 1* / metabolism
Animals
Cytochrome P-450 CYP3A Inhibitors* / chemical synthesis
Cytochrome P-450 CYP3A Inhibitors* / chemistry
Cytochrome P-450 CYP3A Inhibitors* / pharmacology
Cytochrome P-450 CYP3A* / metabolism
Dose-Response Relationship, Drug
Drug Design*
Humans
Male
Mice
Models, Molecular
Molecular Structure
Paclitaxel / chemistry
Paclitaxel / pharmacology
Rats
Structure-Activity Relationship
ortho-Aminobenzoates* / chemical synthesis
ortho-Aminobenzoates* / chemistry
ortho-Aminobenzoates* / pharmacology

Substances

Cytochrome P-450 CYP3A
ortho-Aminobenzoates
ATP Binding Cassette Transporter, Subfamily B, Member 1
Cytochrome P-450 CYP3A Inhibitors
anthranilamide
Paclitaxel
CYP3A4 protein, human