The base-induced regioselective radical arylation of 3-aminochromone with aryl hydrazine.

A simple and efficient direct radical C-2 arylation of 3-aminochromone derivatives with aryl hydrazine is described. The aryl hydrazine acts as an initiator and source for the aryl radical via the cleavage of the C-N bond of aryl hydrazine. The reaction proceeds via a base-promoted single electron transfer (SET) pathway. The aryl radical abstracts a single electron from 3-aminochromone, which generates a C2-radical iminium ion to undergo a cross-coupling reaction with an aryl radical, and this process offers an array of regioselective 2-aryl substituted 3-aminochromones.

Development of potent dopamine-norepinephrine uptake inhibitors (DNRIs) based on a (2S,4R,5R)-2-benzhydryl-5-((4-methoxybenzyl)amino)tetrahydro-2H-pyran-4-ol molecular template.

Current therapy of depression is less than ideal with remission rates of only 25-35% and response rates of 45-60%. It has been hypothesized that a dysfunctional dopaminergic system in the mesocorticolimbic pathway in depressive disorder may lead to development of anhedonia associated with loss of pleasure and interest along with loss of motivation. The current antidepressants do not address dopamine dysfunction which might explain their low efficacy. In this report, we have described an SAR study on our pyran-based triple reuptake inhibitors (TRIs) which are being investigated as the next-generation antidepressants. In the present work we demonstrate that our lead TRIs can be modified with appropriate aromatic substitutions to display a highly potent SSRI profile for compounds 2a and 4a (Ki (SERT); 0.71 and 2.68nM, respectively) or a potent DNRI profile for compounds 6b and 6h (Ki (DAT/NET); 8.94/4.76 and 13/7.37nM, respectively). Compounds 4g-4i exhibited potencies at all three monoamine transporters. The results provide insights into the structural requirements for developing selective dual- and triple-uptake inhibitors from a unique pyran molecular template for an effective management of depression and related disorders.

Phosphazene-Based Covalent Organic Framework as an Efficient Catalyst (COF-1) for the Dehydration of Fructose to 5-HMF.

5-Hydroxymethylfurfural (HMF) is a promising organic platform for producing value-added chemicals. In this work, we focused on using a covalent organic framework (COF-1) as a heterogeneous catalyst for the dehydration of fructose to 5-HMF. The unique phosphazene unit-functionalized pores of COF-1 are essential active sites for catalytic performance. The results show that under the optimized reaction conditions, a maximum yield of 90% was obtained within 1.5 h at 120 °C. Furthermore, the effects of the catalyst load, reaction temperature, and usage of solvents for the improvement of reaction yield were investigated. The catalyst recyclability results showed that the yield of HMF did not change appreciably (90-82%) over five consecutive recycling runs. This work provides a viable strategy by applying phosphazene-based COF-1 for the efficient synthesis of HMF from renewable biomass. The synthesized HMF was further used for the synthesis of the biopolymer monomer furan-2,5-dimethylcarboxylate (FDMC) through N-heterocyclic carbene (NHC)-catalyzed oxidative esterification.

Novel Potent Dopamine-Norepinephrine and Triple Reuptake Uptake Inhibitors Based on Asymmetric Pyran Template and Their Molecular Interactions with Monoamine Transporters.

We have carried out a structural exploration of (2S,4R,5R)-2-(bis(4-fluorophenyl)methyl)-5-((4-methoxybenzyl)amino)tetrahydro-2H-pyran-4-ol (D-473) to investigate the influence of various functional groups on its aromatic ring, the introduction of heterocyclic aromatic rings, and the alteration of the stereochemistry of functional group on the pyran ring. The novel compounds were tested for their affinities for the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) in the brain by measuring their potency in inhibiting monoamine neurotransmitter uptake. Our studies identified some of the most potent dopamine-norepinephrine reuptake inhibitors known to-date like D-528 and D-529. The studies also led to development of potent triple reuptake inhibitors such as compounds D-544 and D-595. A significant influence from the alteration of the stereochemistry of the hydroxyl group on the pyran ring of D-473 on transporters affinities was observed indicating stereospecific preference for interaction. The inhibitory profiles and structure-activity relationship of lead compounds were further corroborated by molecular docking studies at the primary binding sites of monoamine transporters. The nature of interactions found computationally correlated well with their affinities for the transporters.

Synthesis of 4-mercapto-L-lysine derivatives: potential building blocks for sequential native chemical ligation.

A general and diastereoselective synthesis of (2S, 4S)-4-mercapto-L-lysine derivative was described. The key features of this synthesis include Zn-mediated diastereoselective Reformatsky reaction and selective reduction of methyl ester with sodium borohydride. Introduction of thiol functional group on lysine side chain proved to be appropriate for dual native chemical ligation. This methodology allows to develop various 4-substituted L-lysine derivatives.

Development of a Highly Potent D2/D3 Agonist and a Partial Agonist from Structure-Activity Relationship Study of N(6)-(2-(4-(1H-Indol-5-yl)piperazin-1-yl)ethyl)-N(6)-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine Analogues: Implication in the Treatment of Parkinson's Disease.

Our structure-activity relationship studies with N(6)-(2-(4-(1H-indol-5-yl)piperazin-1-yl)ethyl)-N(6)-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine derivatives led to development of a lead compound (-)-21a which exhibited very high affinity (Ki, D2 = 16.4 nM, D3 = 1.15 nM) and full agonist activity (EC50 (GTPγS); D2 = 3.23 and D3 = 1.41 nM) at both D2 and D3 receptors. A partial agonist molecule (-)-34 (EC50 (GTPγS); D2 = 21.6 (Emax = 27%) and D3 = 10.9 nM) was also identified. In a Parkinson's disease (PD) animal model, (-)-21a was highly efficacious in reversing hypolocomotion in reserpinized rats with a long duration of action, indicating its potential as an anti-PD drug. Compound (-)-34 was also able to elevate locomotor activity in the above PD animal model significantly, implying its potential application in PD therapy. Furthermore, (-)-21a was shown to be neuroprotective in protecting neuronal PC12 from toxicity of 6-OHDA. This report, therefore, underpins the notion that a multifunctional drug like (-)-21a might have the potential not only to ameliorate motor dysfunction in PD patients but also to modify disease progression by protecting DA neurons from progressive degeneration.

N-Heterocyclic carbene catalyzed C-glycosylation: a concise approach from Stetter reaction.

Described herein is the first example of an organocatalytic approach for acylanion addition to the anomeric carbon of 2-nitroglucal using an N-heterocyclic carbene catalyst. Control over the reaction conditions gives ß-selective and nitro-eliminated C-glycosides, providing opportunities to produce new classes of C-glycoside.

Direct C-glycosylation of organotrifluoroborates with glycosyl fluorides and its application to the total synthesis of (+)-varitriol.

A mild, stereoselective, and quick approach to accessing alkynyl and alkenyl C-glycosides via BF(3)·Et(2)O promoted coupling of organotrifluoroborates and glycosyl fluorides is reported. The application of this method was further demonstrated by the concise and efficient total synthesis of (+)-varitriol in only seven steps.

N-Heterocyclic carbene-catalyzed intramolecular aldehyde-nitrile cross coupling: an easy access to 3- aminochromones.

An immense effort has been made to develop an efficient strategy for the carbon-carbon bond formation between aldehyde and nitrile intramolecularly using an N-heterocyclic carbene catalyst to derive 3-aminochromone derivatives in good to excellent yields (80-95%).