Design, synthesis and biological evaluation of small molecule inhibitors of CD4-gp120 binding based on virtual screening

LaLonde, Judith M.; Elban, Mark A.; Courter, Joel R.; Sugawara, Akihiro; Soeta, Takahiro; Madani, Navid; Princiotto, Amy M.; Kwon, Young Do; Kwong, Peter D.; Schön, Arne; Freire, Ernesto; Sodroski, Joseph; Smith, Amos B.

doi:10.1016/j.bmc.2010.11.049

Cited by 74 publications

(95 citation statements)

References 40 publications

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“…The resulting phenylpyrrole 13 intermediate was subsequently reduced using a NaBH 4 eCuSO 4 treatment into the attempted 1-(2-amino-4-bromophenyl)pyrrole 14 [18]. Addition of 14 to ethyl chlorooxoacetate in the presence of triethylamine provided the ester 15 [34,35]. The ethyl 7-bromopyrrolo[1,2-a] quinoxaline-4-carboxylate 16 was then prepared by cyclization of the amido-ester 15 in refluxing phosphorus oxychloride [36].…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and biological evaluation of novel substituted pyrrolo[1,2-a]quinoxaline derivatives as inhibitors of the human protein kinase CK2

Guillon¹,

Borgne²,

Rimbault³

et al. 2013

European Journal of Medicinal Chemistry

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a b s t r a c tHerein we describe the synthesis and properties of substituted phenylaminopyrrolo[1,2-a]quinoxalinecarboxylic acid derivatives as a novel class of potent inhibitors of the human protein kinase CK2. A set of 15 compounds was designed and synthesized using convenient and straightforward synthesis protocols. The compounds were tested for inhibition of human protein kinase CK2, which is a potential drug target for many diseases including inflammatory disorders and cancer. New inhibitors with IC 50 in the microand sub-micromolar range were identified. The most promising compound, the 4-[(3-chlorophenyl) amino]pyrrolo[1,2-a]quinoxaline-3-carboxylic acid 1c inhibited human CK2 with an IC 50 of 49 nM. Our findings indicate that pyrrolo[1,2-a]quinoxalines are a promising starting scaffold for further development and optimization of human protein kinase CK2 inhibitors.

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Section: Chemistrymentioning

confidence: 99%

Synthesis and biological evaluation of novel substituted pyrrolo[1,2-a]quinoxaline derivatives as inhibitors of the human protein kinase CK2

Guillon¹,

Borgne²,

Rimbault³

et al. 2013

European Journal of Medicinal Chemistry

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“…NBD-556 binds in a well-conserved pocket on gp120 and can induce conformational changes in gp120 similar to those induced by CD4 (88)(89)(90)(91). Structure-based design has led to the improvement of the affinity and antiviral potency and breadth of the CD4-mimetic compounds (92)(93)(94)(95). Recently developed analogues have been shown to inhibit infection by a range of HIV-1 primary strains (94,95).…”

mentioning

confidence: 99%

Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds

Madani

Princiotto

Easterhoff

et al. 2016

J Virol

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The human immunodeficiency virus (HIV-1) envelope glycoproteins (Env) mediate virus entry through a series of complex conformational changes triggered by binding to the receptors CD4 and CCR5/CXCR4. Broadly neutralizing antibodies that recognize conserved Env epitopes are thought to be an important component of a protective immune response. However, to date, HIV-1 Env immunogens that elicit broadly neutralizing antibodies have not been identified, creating hurdles for vaccine development. Small-molecule CD4-mimetic compounds engage the CD4-binding pocket on the gp120 exterior Env and induce Env conformations that are highly sensitive to neutralization by antibodies, including antibodies directed against the conserved Env region that interacts with CCR5/CXCR4. Here, we show that CD4-mimetic compounds sensitize primary HIV-1 to neutralization by antibodies that can be elicited in monkeys and humans within 6 months by several Env vaccine candidates, including gp120 monomers. Monoclonal antibodies directed against the gp120 V2 and V3 variable regions were isolated from the immunized monkeys and humans; these monoclonal antibodies neutralized a primary HIV-1 only when the virus was sensitized by a CD4-mimetic compound. Thus, in addition to their direct antiviral effect, CD4-mimetic compounds dramatically enhance the HIV-1-neutralizing activity of antibodies that can be elicited with currently available immunogens. Used as components of microbicides, the CD4-mimetic compounds might increase the protective efficacy of HIV-1 vaccines. IMPORTANCEPreventing HIV-1 transmission is a high priority for global health. Eliciting antibodies that can neutralize transmitted strains of HIV-1 is difficult, creating problems for the development of an effective vaccine. We found that small-molecule CD4-mimetic compounds sensitize HIV-1 to antibodies that can be elicited in vaccinated humans and monkeys. These results suggest an approach to prevent HIV-1 sexual transmission in which a virus-sensitizing microbicide is combined with a vaccine.

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“…In a search for novel antimalarial compounds, a series of compounds containing N-ethylpyrrolidine moiety were synthesized and evaluated as antiplasmodial agents 3,4 . Moreover, 2-(aminomethyl)-1-ethylpyrrolidine can be used to synthesize antiviral agents 5,6 , antitumor compounds 7,8 , melanin-concentrating hormone (MCH) receptor 1 antagonists 9 , and Homo sapiens acetylcholinesteraste (hAChE) inhibitor 10 .…”

Section: -(Aminomethyl)-1-ethylpyrrolidinementioning

confidence: 99%

Development of an Efficient HPLC Method With Pre-Column Derivatization for Determination of Enantiomeric Purity of 2-(Aminomethyl)-1-Ethylpyrrolidine

Wang

Yao

Qian

et al. 2015

J. Chil. Chem. Soc.

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The development of a simple and efficient analytical method for determination of enantiomeric purity of 2-(aminomethyl)-1-ethylpyrrolidine was presented. The method was based on pre-column derivatization of 2-(aminomethyl)-1-ethylpyrrolidine with 4-nitrobenzoic acid completing separation of the enantiomers on high performance liquid chromatographic (HPLC) chiral stationary phase (CSP). After optimizing all the effective parameters, the best performances were achieved on a Chiralcel OD-H analytical column (250 × 4.6 mm) using n-hexane: ethanol (98:2, v/v) containing 0.2% triethylamine as mobile phase with a flow rate of 1.0 mL min -1 at 25°C. Online UV and optical rotation (OR) detection was performed at 254 nm. The parameters which have an effect on chiral separation were investigated, including mobile phase additive, organic modifier type and concentration, column temperature and flow rate. The method was tested for precision, accuracy, linearity, limit of detection (LOD), limit of quantification (LOQ) and robustness. The present method is expected to be accurate, stable, rapid and sensitive and can be used for the determination of the enantiomeric purity of 2-(aminomethyl)-1-ethylpyrrolidine in bulk samples.

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Design, synthesis and biological evaluation of small molecule inhibitors of CD4-gp120 binding based on virtual screening

Cited by 74 publications

References 40 publications

Synthesis and biological evaluation of novel substituted pyrrolo[1,2-a]quinoxaline derivatives as inhibitors of the human protein kinase CK2

Synthesis and biological evaluation of novel substituted pyrrolo[1,2-a]quinoxaline derivatives as inhibitors of the human protein kinase CK2

Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds

Development of an Efficient HPLC Method With Pre-Column Derivatization for Determination of Enantiomeric Purity of 2-(Aminomethyl)-1-Ethylpyrrolidine

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