ArticleScientific reports2021
Structure activity relationships and the binding mode of quinolinone-pyrimidine hybrids as reversal agents of multidrug resistance mediated by P-gp.
Article in Scientific reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 33 citations in OpenAlex.
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- Therapeutic Potental of Quinolin-2Mini reviews in medicinal chemistry · 2025Review
- The Structure-Antiproliferative Activity Relationship of Pyridine Derivatives.International journal of molecular sciences · 2024Review
- Novel betulin derivatives as multidrug reversal agents targeting P-glycoprotein.Scientific reports · 2024Article
- Novel Multi-Target Agents Based on the Privileged Structure of 4-Hydroxy-2-quinolinone.Molecules (Basel, Switzerland) · 2023Article
- Advances in the structure, mechanism and targeting of chemoresistance-linked ABC transporters.Nature reviews. Cancer · 2023Review
- Carnosine Potentiates Doxorubicin-Induced Cytotoxicity in Resistant NCI/ADR-RES Cells by Inhibiting P-Glycoprotein-In Silico and In Vitro Evidence.Molecules (Basel, Switzerland) · 2022Article
- Extracts from Argentinian native plants reverse fluconazole resistance in Candida species by inhibiting the efflux transporters Mdr1 and Cdr1.BMC complementary medicine and therapies · 2022Article
- Effects of Myristicin in Association with Chemotherapies on the Reversal of the Multidrug Resistance (MDR) Mechanism in Cancer.Pharmaceuticals (Basel, Switzerland) · 2022Article
- Design and Synthesis of New Pyrimidine-Quinolone Hybrids as NovelPharmaceuticals (Basel, Switzerland) · 2022Article
- Multidrug Resistance of Cancer Cells and the Vital Role of P-Glycoprotein.Life (Basel, Switzerland) · 2022Review
- The thiophene α-terthienylmethanol isolated fromFrontiers in pharmacology · 2022Article
- New Therapeutic Strategy for Overcoming Multidrug Resistance in Cancer Cells with Pyrazolo[3,4-Cancers · 2021Article
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Authors and funding
9 authors at 5 institutions in 3 countries.
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No grant is acknowledged in the PubMed record.
Abstract
P-gp-associated multidrug resistance is a major impediment to the success of chemotherapy. With the aim of finding non-toxic and effective P-gp inhibitors, we investigated a panel of quinolin-2-one-pyrimidine hybrids. Among the active compounds, two of them significantly increased intracellular doxorubicin and rhodamine 123 accumulation by inhibiting the efflux mediated by P-gp and restored doxorubicin toxicity at nanomolar range. Structure-activity relationships showed that the number of methoxy groups, an optimal length of the molecule in its extended conformation, and at least one flexible methylene group bridging the quinolinone to the moiety bearing the pyrimidine favored the inhibitory potency of P-gp. The best compounds showed a similar binding pattern and interactions to those of doxorubicin and tariquidar, as revealed by MD and hybrid QM/MM simulations performed with the recent experimental structure of P-gp co-crystallized with paclitaxel. Analysis of the molecular interactions stabilizing the different molecular complexes determined by MD and QTAIM showed that binding to key residues from TMH 4-7 and 12 is required for inhibition.
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