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

Metal-Free, Ionic Liquid-Mediated Synthesis of Functionalized Quinolines

An expedient and metal-free synthetic protocol for construction of substituted quinolines has been developed from anilines and phenylacetaldehydes using imidazolium cation-based ionic liquids as the reaction medium. Mechanistic analysis indicated that the reaction occurs through C–C and C–N bond formation to produce isolable 2,3-disubstituted quinoline intermediates, which undergo C–C bond cleavage to produce 3-substituted quinolines. The reaction proceeds smoothly with a range of functionalities in good to excellent yields. Advantages of this protocol include metal-free, environmentally friendly, recyclable reaction media, higher yields and shorter reaction times, and thus is promising for the efficient combinatorial synthesis of structurally diverse 2,3-disubstituted and 3-substituted quinolines

Synthesis, and the antioxidant, neuroprotective and P-glycoprotein induction activity of 4-arylquinoline-2-carboxylates

An efficient formic acid catalyzed one-pot synthesis of 4-arylquinoline 2-carboxylates in water via three-component coupling of arylamines, glyoxylates and phenylacetylenes has been described. 4-Arylquinoline 2-carboxylates 1o and 1q displayed significant antioxidant activity as indicated by their Fe-reducing power in the ferric reducing ability of plasma (FRAP) assay. The compounds were found to react directly with hydrogen peroxide, which might be one of the mechanisms of their antioxidant effect. Compounds 1o and 1q effectively quenched H<SUB>2</SUB>O<SUB>2</SUB> and amyloid-β-generated reactive oxygen species (ROS) and also displayed significant protection against H<SUB>2</SUB>O<SUB>2</SUB>-induced neurotoxicity in human neuroblastoma SH-SY5Y cells. Additionally, all compounds exhibited promising P-glycoprotein induction activity in human adenocarcinoma LS-180 cells, indicating their potential to enhance amyloid-β clearance from Alzheimer's brains. Furthermore, all compounds were relatively non-toxic to SH-SY5Y and LS-180 cells (IC₅₀ &#62; 50 μM). The promising antioxidant, ROS quenching, neuroprotective and Pgp-induction activity of these compounds strongly indicate their potential as anti-Alzheimer's agents

<i>ortho</i>-Amidoalkylation of Phenols via Tandem One-Pot Approach Involving Oxazine Intermediate

A new and efficient method for <i>ortho</i>-amidoalkylation of phenols via Mannich-type condensation with formaldehyde and lactams using recyclable solid acid catalyst is described. This is the first report for <i>ortho</i>-amidoalkylation of phenols by lactams via Mannich-type condensation. LC-ESI-MS/MS based mechanistic study revealed that reaction proceeds through <i>o</i>-quinone methide (<i>o</i>-QM) and an oxazine intermediate via tandem Knoevenagel condensation, formal [4 + 2]-Diels–Alder cycloaddition and acid catalyzed oxazine ring-opening

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

Tandem Ring Opening/Intramolecular [2 + 2] Cycloaddition Reaction for the Synthesis of Cyclobutane Fused Thiazolino-2-Pyridones

Reaction of thiazoline fused 2-pyridones with alkyl halides in the presence of cesium carbonate opens the thiazoline ring via S-alkylation and generates N-alkenyl functionalized 2-pyridones. In the reaction with propargyl bromide, the thiazoline ring opens and subsequently closes via a [2 + 2] cycloaddition between an in situ generated allene and the α,β-unsaturated methyl ester. This method enabled the synthesis of a variety of cyclobutane fused thiazolino-2-pyridones, of which a few analogues inhibit amyloid β1–40 fibril formation. Furthermore, other analogues were able to bind mature α-synuclein and amyloid β1−40 fibrils. Several thiazoline fused 2-pyridones with biological activity tolerate this transformation, which in addition provides an exocyclic alkene as a potential handle for tuning bioactivity

K2S2O8-mediated coupling of 6-amino-7-aminomethyl-thiazolino-pyridones with aldehydes to construct amyloid affecting pyrimidine-fused thiazolino-2-pyridones

We herein present the synthesis of diversely functionalized pyrimidine fused thiazolino-2-pyridones via K2S2O8-mediated oxidative coupling of 6-amino-7-(aminomethyl)-thiazolino-2-pyridones with aldehydes. The developed protocol is mild, has wide substrate scope, and does not require transition metal catalyst or base. Some of the synthesized compounds have an ability to inhibit the formation of Amyloid-β fibrils associated with Alzheimer's disease, while others bind to mature amyloid-β and α-synuclein fibrils