56161-70-7

Upstream product

• 21763-01-9 1-phenyl-1-phenoxy-3-chloropropane 
• 74-89-5 methylamine 
• 104-52-9 phenylpropyl chloride 
• 21763-00-8 1-bromo-3-chloro-1-phenylpropane 
• 62872-58-6 3-iodo-1-phenyl-propan-1-ol 
• 57256-93-6 N-methyl-3-chloro-3-phenylpropylamine 
• 108-95-2 phenol 
• 42142-52-9 3-methylamino-1-phenylpropan-1-ol 

Downstream Products

• 1250437-82-1 9,10-dihydro-N-methyl-9-oxo-N-(3-phenoxy-3-phenylpropyl)acridine-4-carboxamide 

Relevant academic research and scientific papers

Tuning the activity of known drugs via the introduction of halogen atoms, a case study of SERT ligands – Fluoxetine and fluvoxamine

The selective serotonin reuptake inhibitors (SSRIs), acting at the serotonin transporter (SERT), are one of the most widely prescribed antidepressant medications. All five approved SSRIs possess either fluorine or chlorine atoms, and there is a limited number of reports describing their analogs with heavier halogens, i.e., bromine and iodine. To elucidate the role of halogen atoms in the binding of SSRIs to SERT, we designed a series of 22 fluoxetine and fluvoxamine analogs substituted with fluorine, chlorine, bromine, and iodine atoms, differently arranged on the phenyl ring. The obtained biological activity data, supported by a thorough in silico binding mode analysis, allowed the identification of two partners for halogen bond interactions: the backbone carbonyl oxygen atoms of E493 and T497. Additionally, compounds with heavier halogen atoms were found to bind with the SERT via a distinctly different binding mode, a result not presented elsewhere. The subsequent analysis of the prepared XSAR sets showed that E493 and T497 participated in the largest number of formed halogen bonds. The XSAR library analysis led to the synthesis of two of the most active compounds (3,4-diCl-fluoxetine 42, SERT Ki = 5 nM and 3,4-diCl-fluvoxamine 46, SERT Ki = 9 nM, fluoxetine SERT Ki = 31 nM, fluvoxamine SERT Ki = 458 nM). We present an example of the successful use of a rational methodology to analyze binding and design more active compounds by halogen atom introduction. ‘XSAR library analysis’, a new tool in medicinal chemistry, was instrumental in identifying optimal halogen atom substitution.

Molecular basis for selective serotonin reuptake inhibition by the antidepressant agent fluoxetine (Prozac)

Inhibitors of the serotonin transporter (SERT) are widely used antidepressant agents, but the structural mechanism for inhibitory activity and selectivity over the closely related norepinephrine transporter (NET) is not well understood. Here we use a combination of chemical, biological, and computational methods to decipher the molecular basis for high-affinity recognition in SERT and selectivity over NET for the prototypical antidepressant drug fluoxetine (Prozac; Eli Lilly, Indianapolis, IN). We show that fluoxetine binds within the central substrate site of human SERT, in agreement with recent X-ray crystal structures of LeuBAT, an engineered monoamine-like version of the bacterial amino acid transporter LeuT. However, the binding orientation of fluoxetine is reversed in our experimentally supported model comparedwith the LeuBAT structures, emphasizing the need for careful experimental verification when extrapolating findings from crystal structures of bacterial transporters to human relatives. We find that the selectivity of fluoxetine and nisoxetine, a NET selective structural congener of fluoxetine, is controlled by residues in different regions of the transporters, indicating a complex mechanism for selective recognition of structurally similar compounds in SERT and NET. Our findings add important new information on the molecular basis for SERT/NET selectivity of antidepressants, and provide the first assessment of the potential of LeuBAT as a model system for antidepressant binding in human transporters, which is essential for future structure-based drug development of antidepressant drugs with fine-tuned transporter selectivity. Copyright

Design, synthesis and evaluation of substituted N-(3-arylpropyl)-9,10- dihydro-9-oxoacridine-4-carboxamides as potent MDR reversal agents in cancer

A novel class of molecules with structure N-(3-arylpropyl)-9,10-dihydro-9- oxoacridine-4-carboxamides (20-29) were designed by generating a pharmacophore for potent MDR reversal activity using phase drug design software. The designed molecules were synthesized by a novel synthesis route and evaluated for their inhibitory effects on the transport activity of P-glycoprotein (P-gp) by standard Hoechst 33342 assay method. Based on the pIC50 values of ten title compounds screened, three compounds exhibited better activity as compared to Verapamil used as standard.

Microwave-assisted synthesis and evaluation of substituted aryl propyl acridone-4-carboxamides as potential chemosensitizing agents for cancer

A novel class of compounds with structure Aryl propyl acridone-4- carboxamides were synthesized by conventional and microwave (MW) irradiation methods and evaluated for their inhibitory effects on the transport activity of P- glycoprotein (P-gp) by standard Hoechst 33342 assay method. The title compounds with phenoxy substitution exhibited better activity.