title: Discovery of 4-acetyl-3-(4-fluorophenyl)-1-(p-tolyl)-5-methylpyrrole as a dual inhibitor of human P-glycoprotein and Staphylococcus aureus Nor A efflux pump.
abstract: Polysubstituted pyrrole natural products, lamellarins, are known to overcome multi-drug resistance in cancer via the inhibition of p-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) efflux pumps. Herein, a series of simplified polysubstituted pyrroles, prepared via a one-pot domino protocol, were screened for P-gp inhibition in P-gp overexpressing human adenocarcinoma LS-180 cells using a rhodamine 123 efflux assay. Several compounds showed the significant inhibition of P-gp at 50 μM, as indicated by increase in the intracellular accumulation of Rh123 in LS-180 cells. Furthermore, pyrrole 5i decreased the efflux of digoxin, a FDA approved P-gp substrate in MDCK-MDR1 cells with an IC50 of 11.2 μM. In in vivo studies, following the oral administration of a P-gp substrate drug, rifampicin, along with compound , the Cmax and AUC0-∞ of rifampicin was enhanced by 31% and 46%, respectively. All the compounds were then screened for their ability to potentiate ciprofloxacin activity via the inhibition of Staphylococcus aureus Nor A efflux pump. Pyrrole showed the significant inhibition of S. aureus Nor A efflux pump with 8- and 4-fold reductions in the MIC of ciprofloxacin at 50 and 6.25 μM, respectively. The molecular docking studies of compound with the human P-gp and S. aureus Nor A efflux pump identified its plausible binding site and key interactions. Thus, the results presented herein strongly indicate the potential of this scaffold for its use as multi-drug resistance reversal agent or bioavailability enhancer.
authors: Medicinal Chemistry Division, CSIR - Indian Institute of Integrative Medicine, Canal Road, Jammu-180001, India. ram@iiim.ac.in sbharate@iiim.ac.in.
authors: Jaideep B
authors: JB
authors: Bharate
authors: Samsher
authors: S
authors: Singh
authors: Abubakar
authors: A
authors: Wani
authors: Sadhana
authors: S
authors: Sharma
authors: Prashant
authors: P
authors: Joshi
authors: Inshad A
authors: IA
authors: Khan
authors: Ajay
authors: A
authors: Kumar
authors: Ram A
authors: RA
authors: Vishwakarma
authors: Sandip B
authors: SB
authors: Bharate
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002939:Ciprofloxacin / Q000494:pharmacology; D003374:Coumarins / Q000138:chemical synthesis / Q000494:pharmacology; D004285:Dogs; D004996:Ethidium / Q000378:metabolism; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics; D013211:Staphylococcus aureus / Q000378:metabolism*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D001426:Bacterial Proteins; D002939:Ciprofloxacin; D003374:Coumarins; D004996:Ethidium; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011758:Pyrroles; D012293:Rifampin; C000604635:4-acetyl-3-(4-fluorophenyl)-1-(p-tolyl)-5-methylpyrrole; C075040:NorA protein, Staphylococcus