Quinazolinone-based fungal efflux pump inhibitors. Part 1: Discovery of an (N-methylpiperazine)-containing derivative with activity in clinically relevant Candida spp.
The discovery of a series of quinazolinone-based fungal efflux pump inhibitors by high-throughput screening for potentiation of fluconazole in C. albicans is described. Attempts to improve the aqueous solubility of screening hits led to the discovery of an analog with greatly improved physical properties and activity against clinically-relevant Candida spp.
Lemoine
Rémy C
RC
Essential Therapeutics, Inc., 850 Maude Ave., Mountain View, CA 94043, USA. remy.lemione@roche.com
Glinka
Tomasz W
TW
Watkins
William J
WJ
Cho
Aesop
A
Yang
Jessie
J
Iqbal
Nadeem
N
Singh
Rajeshwar
R
Madsen
Deidre
D
Lolans
Karen
K
Lomovskaya
Olga
O
Oza
Uma
U
Dudley
Michael N
MN
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002175:Candida / Q000187:drug effects* / Q000201:enzymology; D025141:Drug Resistance, Fungal; D004357:Drug Synergism; D015725:Fluconazole / Q000737:chemistry / Q000494:pharmacology; D005656:Fungal Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D066298:In Vitro Techniques; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents; C094693:CDR1 protein, Candida albicans; D005656:Fungal Proteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D010879:Piperazines; D011799:Quinazolines; D015725:Fluconazole