The dearomatization of indoles represents the most efficient approach for accessing highly valued indolines. The inherent nucleophilic reactivity of indoles has dictated indole dearomatization development in both 1e– and 2e– processes. However, the dearomatization of electron-deficient indoles has been challenging. Herein, we introduce a conceptually distinct photoredox-mediated Giese-type transformation strategy, which is generally used for the conjugate addition of radicals to simple α, β-unsaturated systems, for chemoselectively breaking CC bonds embedded in the aromatic structure. Moreover, highly diastereoselective addition of challenging neutral radicals has been achieved by Oppolzer camphorsultam chiral auxiliary. Structurally diverse amine-functionalized chiral indolines carrying distinct functional and stereochemical diversity are produced from a wide array of amines as radical precursors. Furthermore, the mild, powerful manifold is capable of the late-stage modification of complex natural products and pharmaceuticals. DFT studies are performed to elucidate the observed stereochemical outcomes.

A series of 4-thiazolidinone derivatives were synthesized and evaluated as novel human dihydroorotate dehydrogenase (DHODH) inhibitors. Compounds and displayed IC values of 1.75 and 1.12 μM, respectively. The structure-activity relationship was summarized. Further binding mode analysis revealed that compound could form a hydrogen bond with Tyr38 and a water-mediated hydrogen bond with Ala55, which may be necessary for maintaining the bioactivities of the compounds in this series. Further structural optimization of the- or -position of the phenyl group at R will lead to the identification of more potentDHODH inhibitors.

Human dihydroorotate dehydrogenase (DHODH) is a viable target for the development of therapeutics to treat cancer and immunological diseases, such as rheumatoid arthritis (RA), psoriasis and multiple sclerosis (MS). Herein, a series of acrylamide-based novel DHODH inhibitors as potential RA treatment agents were designed and synthesized. 2-Acrylamidobenzoic acid analog 11 was identified as the lead compound for structure−activity relationship (SAR) studies. The replacement of the phenyl group with naphthyl moieties improved inhibitory activity significantly to double-digit nanomolar range. Further structure optimization revealed that an acrylamide with small hydrophobic groups (Me, Cl or Br) at the 2-position was preferred. Moreover, adding a fluoro atom at the 5-position of the benzoic acid enhanced the potency. The optimization efforts led to potent compounds 42 and 53 ‒ 55 with IC 50 values of 41, 44, 32, and 42 nmol/L, respectively. The most potent compound 54 also displayed favorable pharmacokinetic (PK) profiles and encouraging in vivo anti-arthritic effects in a dose-dependent manner.

2-Aminothiophenes and 2-amino-4,5-dihydrothiophenes were selectively and conveniently synthesized from 4-thiazolidinone derivatives. The meaningful product 10m was efficiently synthesized, which is a commonly-used intermediate for preparing Olanzapine. The present method holds many advantages, such as easy operation, high yields, catalyst-free and using of water as the solvent.

No abstract