Design, Synthesis, and Biological Evaluation of 4-Quinoline Carboxylic Acids as Inhibitors of Dihydroorotate Dehydrogenase

Abstract

We pursued a structure-guided approach toward the development of improved dihydroorotate dehydrogenase (DHODH) inhibitors with the goal of forming new interactions between DHODH and the brequinar class of inhibitors. Two potential residues, T63 and Y356, suitable for novel H-bonding interactions, were identified in the brequinar-binding pocket. Analogues were designed to maintain the essential pharmacophore and form new electrostatic interactions through strategically positioned H-bond accepting groups. This effort led to the discovery of potent quinoline-based analogues 41 (DHODH IC = 9.71 ± 1.4 nM) and 43 (DHODH IC = 26.2 ± 1.8 nM). A cocrystal structure between 43 and DHODH depicts a novel water mediated H-bond interaction with T63. Additional optimization led to the 1,7-naphthyridine 46 (DHODH IC = 28.3 ± 3.3 nM) that forms a novel H-bond with Y356. Importantly, compound 41 possesses significant oral bioavailability ( F = 56%) and an elimination t = 2.78 h (PO dosing). In conclusion, the data supports further preclinical studies of our lead compounds toward selection of a candidate for early-stage clinical development.

New Quinoline-Based Heterocycles as Anticancer Agents Targeting Bcl-2

“…Elemental analysis (% CHN) was run by combustion analysis through an outsourced service (Medac Ltd, Surrey, UK). Commercial compounds were used as received; 2-(4-bromophenyl)quinoline-4-carboxylic acid ( 3a ) [20] and 2-(4-bromophenyl)-6-methoxyquinoline-4-carboxylic acid ( 3b ) [21] were accessed via the standard Pfitzinger reaction protocol [8].…”

A novel series of human dihydroorotate dehydrogenase inhibitors discovered by in vitro screening: inhibition activity and crystallographic binding mode

“…Recently, a series of hDHODH inhibitors were discovered by scaffold-hopping strategy or structural modification based on previous reported lead compounds [16,17] In our instance, the active compounds were selected based on in vitro screening. Our screening discovered a novel class of human DHODH inhibitors, which have a 6-isopropyl-1,5,6,7-tetrahydro-4Hbenzo[d] [1,2,3]triazol-4-one scaffold.…”

Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis

“… 41 reported that inhibition of DHODH can overcome differentiation blockade in AML. There were also promising DHODH inhibitors in the preclinical stage such as S312 ( 8 ) which is reported to display broad-spectrum antiviral activities against various RNA viruses including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 . Besides, the new roles of DHODH in various cancer types were also uncovered in recent years 50 , 51 , 52 , 53 , 54 , 55 .…”