A5050241183- HIV/AIDS drug development and treatment
- Synthesis and Characterization of Heterocyclic Compounds
- Click Chemistry and Applications
- Quinazolinone synthesis and applications
- Biochemical and Molecular Research
- Synthesis and Biological Evaluation
- HIV Research and Treatment
- Synthesis and biological activity
- Receptor Mechanisms and Signaling
- Peptidase Inhibition and Analysis
- Mosquito-borne diseases and control
- Chemical Synthesis and Analysis
- Neuropeptides and Animal Physiology
- Tuberculosis Research and Epidemiology
- Acute Myeloid Leukemia Research
- Carbohydrate Chemistry and Synthesis
- Pharmacological Receptor Mechanisms and Effects
- Parkinson's Disease Mechanisms and Treatments
- Lysosomal Storage Disorders Research
- Synthesis and Reactivity of Heterocycles
- Alzheimer's disease research and treatments
- RNA Interference and Gene Delivery
- Neurotransmitter Receptor Influence on Behavior
- Neuroscience and Neuropharmacology Research
- Adenosine and Purinergic Signaling
Southern Research Institute
2014-2024
Case Western Reserve University
2023
National Institute on Drug Abuse
2015
National Institutes of Health
2015
Laboratoire de Chimie Organique
2000-2007
Université Ibn Zohr
2002-2004
Cadi Ayyad University
2001
Highlights•The small molecule SRI-37330 inhibits TXNIP expression in mouse and human islets•SRI-37330 decreases glucagon secretion action blocks hepatic glucose output•Oral reverses obesity- STZ-induced diabetes steatosis mice•Its antidiabetic effects safety profile make an attractive drug candidateSummaryDiabetes is characterized by hyperglycemia, loss of functional islet beta cell mass, deficiency glucose-lowering insulin, persistent alpha gluconeogenic glucagon. Still, no therapies that...
The G2019S mutation in LRRK2 is one of the most common known genetic causes neurodegeneration and Parkinson disease (PD). mutations are thought to enhance kinase activity. Efficacious small molecule inhibitors with favorable drug properties have recently been developed for pre-clinical studies rodent models, advanced safety trials humans. Rats that express human G2019S-LRRK2 protein knock-in mice provide newly characterized models better understand ostensible target inhibitors. Herein, we...
Novel allosteric modulators of the dopamine transporter (DAT) have been identified. We shown previously that SRI-9804 [<i>N</i>-(diphenylmethyl)-2-phenyl-4-quinazolinamine], SRI-20040 [<i>N</i>-(2,2-diphenylethyl)-2-phenyl-4-quinazolinamine], and SRI-20041 [<i>N</i>-(3,3-diphenylpropyl)-2-phenyl-4-quinazolinamine] partially inhibit [<sup>125</sup>I]RTI-55 ([<sup>125</sup>I]3<i>β</i>-(4′-iodophenyl)tropan-2<i>β</i>-carboxylic acid methyl ester) binding [<sup>3</sup>H]dopamine...
Zebrafish are a powerful tool for studying muscle function owing to their high numbers of offspring, low maintenance costs, evolutionarily conserved functions, and the ability rapidly take up small molecular compounds during early larval stages. Fukutin-related protein (FKRP) is putative glycosyltransferase that functions in Golgi apparatus modify sugar chain molecules newly translated proteins. Patients with mutations FKRP gene can have wide spectrum clinical symptoms varying muscle, eye,...
A benzo[6]annulene, 4-(tert-butyl)-N-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl) benzamide (1a), was identified as an inhibitor against Chikungunya virus (CHIKV) with antiviral activity EC90 = 1.45 μM and viral titer reduction (VTR) of 2.5 log at 10 no observed cytotoxicity (CC50 169 μM) in normal human dermal fibroblast cells. Chemistry efforts to improve potency, efficacy, drug-like properties 1a resulted a novel lead compound 8q, which possessed excellent cellular (EC90 270 nM VTR 4.5...
HIV-1 Nef is an attractive target for antiretroviral drug discovery because of its role in promoting infectivity, replication, and host immune system avoidance. Here, we applied a screening strategy which recombinant protein was coupled to activation the Src-family tyrosine kinase Hck, enhances life cycle macrophages. stimulates Hck activity
A small library of ninety four uridine antibiotic analogs was synthesized, under the Pilot Scale Library (PSL) Program NIH Roadmap initiative, from amine 2 and carboxylic acids 33 77 in solution-phase fashion. Diverse aldehyde, sulfonyl chloride, acid reactant sets were condensed to 2, leading after acid-mediated hydrolysis, targeted compounds 3-32 good yields high purity. Similarly, treatment with diverse amines sulfonamides gave 34-75. The coupling amino terminus d-phenylalanine methyl...
// Yonghe Li 1 , Wenyan Lu Surendra K. Saini Omar Moukha-Chafiq Vibha Pathak Subramaniam Ananthan Drug Discovery Division, Southern Research Institute, Birmingham, AL 35205, United States of America Correspondence to: Li, e-mail: yli@southernresearch.org Ananthan, sananthan@southernresearch.org Keywords: Wnt signaling, inhibitor, quinazoline, colorectal cancer, drug discovery Received: July 29, 2015 Accepted: January 13, 2016 Published: 25, ABSTRACT The Wnt/β-catenin signaling pathway is...
The delta opioid receptor (DOR) is a crucial system that regulates pain, mood, anxiety, and similar mental states. DOR agonists, such as SNC80, DOR-neutral antagonists, naltrindole, were developed to investigate the in vivo potential therapeutics for pain depression. However, few inverse agonists non-competitive/irreversible antagonists have been developed, none are widely available. This leaves gap our pharmacological toolbox limits ability biology of this receptor. Thus, we designed...
The disruption of dopamine (DA) neurotransmission by the HIV-1 transactivator transcription (Tat) during infection has been linked to development neurocognitive disorders, even under combined antiretroviral therapy treatment. We have demonstrated that Southern Research Institute (SRI) 32742, a novel allosteric modulator DA transporter (DAT), attenuates cocaine- and Tat-binding DAT, alleviates Tat-induced cognitive deficits potentiation cocaine reward in inducible Tat transgenic mice. current...
Venezuelan equine encephalitis virus (VEEV) is a reemerging alphavirus that can cause resulting in severe human morbidity and mortality. Using high-throughput cell-based screen, we identified quinolinone compound protected against VEEV-induced cytopathic effects. Analysis of viral replication cells several compounds with potent inhibitory activity vaccine virulent strains VEEV. These quinolinones also displayed additional alphaviruses, such as Mayaro Ross River virus, although the potency...
A library of eighty one adenosine antibiotic analogs was prepared under the Pilot Scale Library Program NIH Roadmap initiative from 5′-amino-5′-deoxy-2′,3′-O-isopropylidene-adenosine 3. Diverse aldehyde, sulfonyl chloride and carboxylic acid reactant sets were condensed to 3, in solution-phase fashion, leading after acid-mediated hydrolysis targeted compounds good yields high purity. No marked antituberculosis or anticancer activity noted on preliminary cellular testing, but these nucleoside...
The chemical synthesis of some 4-substituted 1-[1-(2-hydroxyethoxy)-methyl-1,2.3-triazol-(4 and 5)-ylmethyl]-1-H-pyrazolo[3,4-d]pyrimidines 12a,b, 13a,b 14-23 as acyclic nucleosides is described. Treatment (2-acetoxyethoxy)methylbromide with sodium azide afforded (2-acetoxyethoxy)methylazide 9. heterocycles 6a,b were alkylated, separately, propargyl bromide to obtain. regioselectively, 4-(methyl benzyl)thio-1-(prop-2-ynyl)-1H-pyrazolo[3,4-d]pyrimidines 7a,b. These N-alkylated products...
A useful route to obtain trisubstituted pyrazolo[3,4-d]pyrimidines 14-17 is described. Those later were coupled with the alkylating agents 18-20 as in ACV, HBG, and iso-DHPG give, after deprotection, desired acylonucleosides 33-44. Almost all of new compounds evaluated for their inhibitory effects against replication various DNA viruses culture.
The reaction of 1H-pyrazolo[3,4-d]pyrimidin-4,6-dithione 11 with compounds 12a–c produces ethyl α-[6-(1′-carboethoxyalkylthio)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]thioalkylates 13a–c, respectively. These heterocycles were alkylated, separately, alkylating agents 14, 15, and 16 to afford, predominately, the N1-acyclic nucleosides (17–19)a–c, which deprotected give desired products (20–22)a–c. All synthetic characterized on basis their physical spectroscopic properties. acyclic (20–22)a–c...
AbstractA small library of peptidyl adenosine antibiotic analogs was synthesized, under the Pilot Scale Library Program NIH Roadmap initiative, from 2′,3′-O-isoproylideneadenosine-5′-carboxylic acid 2 in excellent yield. The coupling amino terminus L-2-aminophenylbutyric methyl ester to a free 5′-carboxylic moiety followed by sodium hydroxide treatment led carboxylic analog 4. Hydrolysis this latter gave unprotected nucleoside 5. Intermediate 4 served as precursor for preparation novel 6–18...
ABSTRACT The chemical synthesis of some acyclic α-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)thioalkylamide nucleosides (10–12)a–c is described. treatment 1H-pyrazolo[3,4-d]pyrimidin-4-thione 1 with compounds 2a–c gave, regioselectively, ethyl α-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)thioalkylates 3a-c, respectively. These heterocycles were alkylated, separately, alkylating agents 4, 5 and 6 to give, the N1-acyclic (7-9)a-c which deprotected afford desired products (10-12)a-c. All synthetic characterized...
The chemical synthesis and biological evaluation of some acyclic alpha-[6-(1'-carbamoylalkylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]thioalkylamide nucleosides are described.
A small library of fifty-five adenosine peptide analogs was synthesized, under the Pilot Scale Library (PSL) Program NIH Roadmap initiative, from 2′,3′-O-isopropylideneadenosine-5′-carboxylic acid 2. The coupling amine or sulfanilamide reactants to free 5′-carboxylic moiety 2, in automated solution-phase fashion, led after acid-mediated hydrolysis target compounds 3–57 good yields and high purity. No marked anticancer antimalarial activity noted on preliminary cellular testing. Initial...
The synthesis of some acyclic alpha-(pyrazolo[3,4-d]pyrimidin-4-ylthio)alkylamide nucleosides is described.