Investigating the structure-activity relationships of N’ -[(5-nitrofuran-2-yl) methylene] substituted hydrazides against Trypanosoma cruzi to design novel active compounds

Recent advances in combinatorial chemistry have resulted in the rapid screening of libraries against biological targets. Another advance in biological screening is the ability to design and utilize novel, automated, nonradioactive assays for targets of pharmaceutical interest. Using encoding technology and europium time-resolved fluorescence, we have designed primary receptor binding assays to define active compounds against the neurokinin-1 and neurokinin-2 receptor subtypes. In addition, a secondary, cell-based, functional assay measuring intracellular calcium flux with calcium sensitive fluorophores was used to determine receptor agonist or antagonist activities. We adapted a cuvette based assay to a CCD camera and digital imaging system that allowed us to demonstrate functional receptor antagonist activity in all 96 wells of a microtiter plate simultaneously. The screening of a 20,000 member library using europium labeled neurokinin ligands resulted in the identification of 43 active compounds for neurokinin-1 and 27 for neurokinin-2. Through medicinal chemistry and structure-activity relationships, a compound was synthesized with balanced dual antagonist activity at both neurokinin receptors with greater than 100-fold less activity against the neurokinin-3 receptor subtype. The structure-activity relationships generated from this initial library can now be used to design a new focused library to improve on neurokinin-1/neurokinin-2 receptor potency and selectivity.

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Second generation of 5-ethenylbenzofuroxan derivatives as inhibitors of Trypanosoma cruzi growth: Synthesis, biological evaluation, and structure–activity relationships

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2007.01.009 ◽

2007 ◽

Vol 15 (7) ◽

pp. 2768-2781 ◽

Cited By ~ 33

Author(s):

Williams Porcal ◽

Paola Hernández ◽

Gabriela Aguirre ◽

Lucía Boiani ◽

Mariana Boiani ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Second Generation ◽

Biological Evaluation ◽

Structure Activity Relationships ◽

Structure Activity

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Antimycobacterial Activities of Novel 5-(1H-1,2,3-Triazolyl)Methyl Oxazolidinones

Tuberculosis Research and Treatment ◽

10.1155/2012/289136 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Oludotun Adebayo Phillips ◽

Edet Ekpenyong Udo ◽

Reny Varghese

Keyword(s):

Mycobacterium Tuberculosis ◽

Vero Cells ◽

Antibacterial Activities ◽

Mice Model ◽

Active Compounds ◽

Structure Activity Relationships ◽

Structure Activity

The antibacterial activities of a series of triazolyl oxazolidinones againstMycobacterium tuberculosisstrainin vitroandin vivoin a mice model are presented. Most active compounds were noncytotoxic against VERO cells with acceptable selectivity indexes (SI) as measures of compound tolerability. Structure activity relationships (SARs) revealed that analogs with alkylcarbonyl (IC90: < 0.2 to 0.422 μg/mL) and arylcarbonyl (IC90: < 0.2 to 2.103 μg/mL) groups at the piperazine 4N-position-displayed potent antimycobacterium activities, comparable to the methanesulfonyl (IC90: < 0.2 μg/mL) analog, linezolid (IC90: < 0.2 μg/mL), and isoniazid (IC90: < 0.034 μg/mL). The furanylcarbonyl derivative also displayed potent activity, while the arylsulfonyl analogs were inactive. Of the triazolyl oxazolidinones, the morpholino (PH-27) derivative with medium bioavailability in plasma was most activein vivo, but relatively less efficacious than isoniazid.

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