Selective, C-3 Friedel-Crafts acylation to generate functionally diverse, acetylated Imidazo[1,2-a]pyridine derivatives.

Carbon-carbon bonds are integral for pharmaceutical discovery and development. Frequently, C-C bond reactions utilize expensive catalyst/ligand combinations and/or are low yielding, which can increase time and expenditures in pharmaceutical development. To enhance C-C bond formation protocols, we developed a highly efficient, selective, and combinatorially applicable Friedel-Crafts acylation to acetylate the C-3 position of imidazo[1,2-a]pyridines. The reaction, catalyzed by aluminum chloride, is both cost effective and more combinatorial friendly compared to acetylation reactions requiring multiple, stoichiometric equivalents of AlCl3. The protocol has broad application in the construction of acetylated imidazo[1,2-a]pyridines with an extensive substrate scope. All starting materials are common and the reaction requires inexpensive, conventional heating methods for adaptation in any laboratory. Further, the synthesized compounds are predicted to possess GABA activity through a validated, GABA binding model. The developed method serves as a superior route to generate C-3 acetylated imidazo[1,2-a]pyridine building-blocks for combinatorial synthetic efforts.

Rational Design, Synthesis and Biological Evaluation of Pyrimidine-4,6-diamine derivatives as Type-II inhibitors of FLT3 Selective Against c-KIT.

FMS-like Tyrosine Kinase 3 (FLT3) is a clinically validated target for acute myeloid leukemia (AML). Inhibitors targeting FLT3 have been evaluated in clinical studies and have exhibited potential to treat FLT3-driven AML. A frequent, clinical limitation is FLT3 selectivity, as concomitant inhibition of FLT3 and c-KIT is thought to cause dose-limiting myelosuppression. Through a rational design approach, novel FLT3 inhibitors were synthesized employing a pyridine/pyrimidine warhead. The most potent compound identified from the studies is compound 13a, which exhibited an IC50 value of 13.9 ± 6.5 nM against the FLT3 kinase with high selectivity over c-KIT. Mechanism of action studies suggested that 13a is a Type-II kinase inhibitor, which was also supported through computer aided drug discovery (CADD) efforts. Cell-based assays identified that 13a was potent on a variety of FLT3-driven cell lines with clinical relevance. We report herein the discovery and therapeutic evaluation of 4,6-diamino pyrimidine-based Type-II FLT3 inhibitors, which can serve as a FLT3-selective scaffold for further clinical development.

Silver(I)-Catalyzed Regioselective Construction of Highly Substituted α-Naphthols and Its Application toward Expeditious Synthesis of Lignan Natural Products.

A novel route has been developed for regioselective synthesis of highly substituted α-naphthols, binaphthols, and anthracenol through silver(I) catalyzed C(sp(3))-H/C(sp)-H, C(sp(2))-H/C(sp)-H functionalization of ß-ketoesters and alkynes, respectively, in a single step using water as a solvent. This protocol exhibited broad substrate scope and paved the way for synthesis of anticancer arylnaphthalene lignan natural products such as diphyllin, taiwanin E, and justicidin A with excellent selectivity.

Copper(II) catalyzed expeditious synthesis of furoquinoxalines through a one-pot three-component coupling strategy.

Microwave assisted one-pot transformation has been developed for the synthesis of biologically significant polysubstituted furoquinoxalines in good to excellent yields through a copper(II) catalyzed three-component coupling of o-phenylenediamine, ethylglyoxalate, and terminal alkyne, known as A(3)-coupling, followed by 5-endo-dig cyclization.

Molecular iodine promoted divergent synthesis of benzimidazoles, benzothiazoles, and 2-benzyl-3-phenyl-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazines.

An unprecedented formation of a new class of 2-benzyl-3-phenyl-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazines has been discovered during the course of benzimidazole and benzothiazole synthesis, through the molecular iodine-mediated oxidative cyclization with a new C-N and S-N bond formation at ambient temperature.