Synthesis and Structure–Activity Relationship Studies of Pyrido [1,2-e]Purine-2,4(1H,3H)-Dione Derivatives Targeting Flavin-Dependent Thymidylate Synthase in Mycobacterium tuberculosis

In 2002, a new class of thymidylate synthase (TS) involved in the de novo synthesis of dTMP named Flavin-Dependent Thymidylate Synthase (FDTS) encoded by the thyX gene was discovered; FDTS is present only in 30% of prokaryote pathogens and not in human pathogens, which makes it an attractive target for the development of new antibacterial agents, especially against multi-resistant pathogens. We report herein the synthesis and structure-activity relationship of a novel series of hitherto unknown pyrido[1,2-e]purine-2,4(1H,3H)-dione analogues. Several synthetics efforts were done to optimize regioselective N¹-alkylation through organopalladium cross-coupling. Modelling of potential hits were performed to generate a model of interaction into the active pocket of FDTS to understand and guide further synthetic modification. All those compounds were evaluated on an in-house in vitro NADPH oxidase assays screening as well as against Mycobacterium tuberculosis ThyX. The highest inhibition was obtained for compound 23a with 84.3% at 200 µM without significant cytotoxicity (CC₅₀ > 100 μM) on PBM cells.     

Alkynyl-Protected Chiral Bimetallic Ag22Cu7 Superatom with Multiple Chirality Origins

Understanding the origin of chirality in the nanostructured materials is essential for chiroptical and catalytic applications. Here we report a chiral AgCu superatomic cluster, [Ag₂₂Cu₇(C≡CR)₁₆(PPh₃)₅Cl₆](PPh₄), Ag₂₂Cu₇ , protected by an achiral alkynyl ligand (HC≡CR: 3,5-bis(trifluoromethyl)phenylacetylene). Its crystal structure comprises a rare interpenetrating biicosahedral Ag₁₇Cu₂ core, which is stabilized by four different types of motifs: one Cu(C≡CR)₂, four −C≡CR, two chlorides and one helical Ag₅Cu₄(C≡CR)₁₀(PPh₃)₅Cl₄. Structural analysis reveals that Ag₂₂Cu₇ exhibits multiple chirality origins, including the metal core, the metal-ligand interface and the ligand layer. Furthermore, the circular dichroism spectra of R/S-Ag₂₂Cu₇ are obtained by employing appropriate chiral molecules as optical enrichment agents. DFT calculations show that Ag₂₂Cu₇ is an eight-electron superatom, confirm that the cluster is chirally active, and help to analyze the origins of the circular dichroism.