Nefzi, Adel
- Research Professor, Center for Translational Science , Office of Research and Economic Development

Overview
overview
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The development of new pharmacologic agents requires extensive explorations of the chemical space to transform an initial hit compound into a potent and selective chemical probe, or optimize it into a chemical entity with desirable drug-like properties. Our laboratory research interests are in the broadly defined fields of organic synthesis and medicinal chemistry. Our efforts over the past twenty-five years have been focused on the design and the diversity-oriented synthesis of small molecule, peptidomimetic, peptide and cyclic peptide combinatorial libraries and their application in drug discovery. The small molecules libraries are designed to follow known drug-likeness rules including “Lipinski’s Rule of Five”. Our team aims to discover and synthesize biologically active small molecules as research tools and drug leads.
Our compound library collection of small molecule compounds consists of more than 35 million compounds designed around 85 molecular scaffolds systematically arranged in positional scanning and scaffold ranking formats. These formats allow for the analysis of millions of compounds through the use of just hundreds to thousands of samples. The large numbers of chemical libraries of linear and cyclic peptides, non-peptide oligomers, peptidomimetics, small-molecules, and natural product-like organic molecules provide for an exponential increase in screening efficiencies, rich initial SAR, and a unique chemical space while maintaining critical drug like chemical properties. In addition to our mixture-based libraries, we have a large selection of drug like individual small molecule heterocyclic compounds (>10,000) carefully selected from lead-like chemotypes. These compounds are available for high-throughput screening (HTS) and high-content screening (HCS). All compounds have been plated in 96-well plates at 10 mM concentration in DMSO and can be swiftly supplied in different customized formats.
As evidenced by the group publication’s record, the synthetic libraries developed have impacted numerous fields of human health, including cancer, inflammation, pain, diabetes, CNS disorders, antimalarial, and bacterial resistance. Dr. Nefzi research has been supported by the National Institute of Health (NIH), the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute on Drug Abuse (NIDA), the National Cancer Institute (NCI), the National Institute of Aging (NIA) and the National Science Foundation (NSF).
research interests
- Diverse small molecule, peptide, cyclic peptide and peptidomimetic libraries for phenotypic screening, deconvolution of active libraries for identification of active compounds, structure activity relationship (SAR) development: hit to lead optimization, target-based approach for the design and synthesis of “drug-like” molecules, target-based drug design integrated with molecular modeling, scale-up to support in vitro and in vivo efficacy models, development of robust synthetic procedures for scale-up, analytical chemistry support, including drug stability, solubility and structural determinations.
Scholarly & Creative Works
selected publications
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Article
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2021Encoding mu-opioid receptor biased agonism with interaction fingerprintsFull Text via DOI: 10.1007/s10822-021-00422-5 Web of Science: 000712176800001
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2021Discovery of a Lead Compound for Specific Inhibition of Type I Collagen Production in FibrosisFull Text via DOI: 10.1021/acsmedchemlett.1c00006 Web of Science: 000629174700018
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2020Discovery of cyclic guanidine-linked sulfonamides as inhibitors of LMTK3 kinaseFull Text via DOI: 10.1016/j.bmcl.2020.127108 Web of Science: 000522861200012
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2019Antinociceptive activity of thiazole-containing cyclized DAMGO and Leu-(Met) enkephalin analogsFull Text via DOI: 10.1039/c9ob00882a Web of Science: 000471015200015
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2019Identification of Bis-Cyclic Guanidines as Antiplasmodial Compounds from Positional Scanning Mixture-Based LibrariesFull Text via DOI: 10.3390/molecules24061100 Web of Science: 000465503800076
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2018Scaffold Ranking and Positional Scanning Identify Novel Neurite Outgrowth Promoters with Nanomolar PotencyFull Text via DOI: 10.1021/acsmedchemlett.8b00425 Web of Science: 000447471800021
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2018Synthesis of Novel Oxazolyl Amino Acids and Their Use in the Parallel Synthesis of Disubstituted Oxazole LibrariesFull Text via DOI: 10.1055/s-0036-1589148 Web of Science: 000427997500016
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2016Inhibition of methicillin-resistant Staphylococcus aureus (MRSA) by antimicrobial peptides (AMPs) and plant essential oilsFull Text via DOI: 10.1080/13880209.2016.1190763 Web of Science: 000389443300045
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2016Synthesis and antitubercular activity of 1,2,4-trisubstitued piperazinesFull Text via DOI: 10.1016/j.bmcl.2016.03.063 Web of Science: 000373739700021
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2015Identification of Small Molecule Inhibitors of Human As(III) S-Adenosylmethionine Methyltransferase (AS3MT)Full Text via DOI: 10.1021/acs.chemrestox.5b00432 Web of Science: 000367118000019
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2015Combinatorial Libraries As a Tool for the Discovery of Novel, Broad-Spectrum Antibacterial Agents Targeting the ESKAPE PathogensFull Text via DOI: 10.1021/jm501628s Web of Science: 000353602200006
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2015A convenient synthesis of 3,4-cis-disubstituted pyrrolidin-2-onesFull Text via DOI: 10.1016/j.tetlet.2014.11.023 Web of Science: 000348259800015
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2015Easy Conversion of Dimethyl -(Bromomethyl)fumarate into Functionalized Allyl Ethers Mediated by DABCOFull Text via DOI: 10.1080/00397911.2015.1093144 Web of Science: 000365095000011
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2014Substituted dithiazole piperazine benzamides as novel amyloid beta peptide reducing agentsFull Text via DOI: 10.1016/j.bmcl.2014.08.022 Web of Science: 000341435000006
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2014AlphaLISA-based high-throughput screening assay to measure levels of soluble amyloid precursor protein alphaFull Text via DOI: 10.1016/j.ab.2014.05.007 Web of Science: 000338406500004
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2014Combinatorial Synthesis of Oxazol-Thiazole Bis-Heterocyclic CompoundsFull Text via DOI: 10.1021/co400133a Web of Science: 000329879700006
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2013Scaffold Ranking and Positional Scanning Utilized in the Discovery of nAChR-Selective Compounds Suitable for Optimization StudiesFull Text via DOI: 10.1021/jm401543h Web of Science: 000329331600020
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2013Parallel synthesis of bis-oxazole peptidomimeticsFull Text via DOI: 10.1016/j.tetlet.2013.10.078 Web of Science: 000327577200021
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2013Antimalarial and cytotoxic activities of chiral triaminesFull Text via DOI: 10.1016/j.bmcl.2013.06.035 Web of Science: 000322611900017
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2013Striking reduction of amyloid plaque burden in an Alzheimer's mouse model after chronic administration of carmustineFull Text via DOI: 10.1186/1741-7015-11-81 Web of Science: 000318938000001
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2013Hantzsch Based Macrocyclization Approach for the Synthesis of Thiazole Containing CyclopeptidesFull Text via DOI: 10.1007/978-1-62703-652-8_1 Web of Science: 000335641200002
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2012Parallel synthesis of structurally diverse aminobenzimidazole tethered sultams and benzothiazepinonesFull Text via DOI: 10.1016/j.tetlet.2012.09.135 Web of Science: 000312231400006
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2012Prediction of the experimental regioselectivity of C-60 fullerene bis-adductsFull Text via DOI: 10.1002/poc.2943 Web of Science: 000310486900004
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2012Ugi four-center three-component reaction for the parallel solid-phase synthesis of N-substituted thiomopholinonesFull Text via DOI: 10.1016/j.tetlet.2011.12.074 Web of Science: 000301833600002
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2012Parallel Synthesis of Aminobenzimidazole-Tethered ThiazolesFull Text via DOI: 10.1055/s-0031-1289644 Web of Science: 000300198400007
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2011Potent antimicrobial small molecules screened as inhibitors of tyrosine recombinases and Holliday junction-resolving enzymesFull Text via DOI: 10.1007/s11030-011-9333-2 Web of Science: 000300364700017
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2011Integrating Virtual Screening and Combinatorial Chemistry for Accelerated Drug DiscoveryFull Text via DOI: 10.2174/138620711795767866 Web of Science: 000292772100004
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2011Integrating computational and mixture-based screening of combinatorial librariesFull Text via DOI: 10.1007/s00894-010-0850-1 Web of Science: 000291041800025
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2011Increased Diversity of Libraries from Libraries: Chemoinformatic Analysis of Bis-Diazacyclic LibrariesFull Text via DOI: 10.1111/j.1747-0285.2011.01100.x Web of Science: 000289474100004
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2010Two-Step Hantzsch Based Macrocyclization Approach for the Synthesis of Thiazole-Containing CyclopeptidesFull Text via DOI: 10.1021/jo1016822 Web of Science: 000284080300055
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2010Diversity-oriented synthesis of N-aryl-N-thiazolyl compoundsFull Text via DOI: 10.1016/j.tetlet.2010.06.117 Web of Science: 000281356700002
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2010Small molecule functional analogs of peptides that inhibit lambda site-specific recombination and bind Holliday junctionsFull Text via DOI: 10.1016/j.bmcl.2010.06.029 Web of Science: 000279866300053
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2010Parallel synthesis of 19-membered ring macro-heterocycles via intramolecular thioether formationFull Text via DOI: 10.1016/j.tetlet.2010.05.029 Web of Science: 000279340000001
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2010Solid-Phase Synthesis of N-Substituted Pyrrolidinone-Tethered N-Substituted Piperidines via Ugi ReactionFull Text via DOI: 10.1021/cc100054u Web of Science: 000279618200025
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2010ChemInform Abstract: Mixture‐Based Synthetic Combinatorial LibrariesFull Text via DOI: 10.1002/chin.199949239
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2010Synthesis of Chiral PolyaminothiazolesFull Text via DOI: 10.1021/cc9001907 Web of Science: 000277355600003
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2010Conformational landscape of platinum(II)-tetraamine complexes: DFT and NBO studiesFull Text via DOI: 10.1007/s10822-010-9328-6 Web of Science: 000276965100005
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2009Parallel synthesis of chiral pentaamines and pyrrolidine containing bis-heterocyclic libraries. Multiple scaffolds with multiple building blocks: A double diversity for the identification of new antitubercular compoundsFull Text via DOI: 10.1016/j.bmcl.2009.07.010 Web of Science: 000268863800063
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2009Identification, structure-activity relationships and molecular modeling of potent triamine and piperazine opioid ligandsFull Text via DOI: 10.1016/j.bmc.2009.06.026 Web of Science: 000268099700026
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2009Synthetic Small-Molecule Prohormone Convertase 2 InhibitorsFull Text via DOI: 10.1124/mol.108.051334 Web of Science: 000263559500019
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2009Saoussanabiloide, a novel antifungal alkaloid from Echiochilon fruticosum Desf. growing in TunisiaFull Text via DOI: 10.1080/14786410802267619 Web of Science: 000273303000002
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2006Synthesis of platinum(II) chiral tetraamine coordination complexesFull Text via DOI: 10.1021/cc060045h Web of Science: 000240403200020
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2006A versatile access to new macrocyclic oligoheterocycles (MOH)Full Text via DOI: 10.1016/j.bmcl.2006.04.039 Web of Science: 000238182700001
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2006Efficient approach for the parallel solid-phase synthesis of 1,1,3,4-tetrasubstituted-5-oxopiperazin-1-ium compoundsFull Text via DOI: 10.1016/j.tetlet.2006.03.196 Web of Science: 000237820800003
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2005Inhibitors of XIAP sensitize CD40-activated chronic lymphocytic leukemia cells to CD95-mediated apoptosisFull Text via DOI: 10.1182/blood-2005-02-0695 Web of Science: 000231495000040
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2005Small-molecule XIAP inhibitors derepress downstream effector caspases and induce apoptosis of acute myeloid leukemia cellsFull Text via DOI: 10.1182/blood-2004-08-3168 Web of Science: 000229009000050
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2004Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activityFull Text via DOI: 10.1016/S1535-6108(03)00332-5 Web of Science: 000188400300007
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2003Efficient approach for the diversity-oriented synthesis of macro-heterocycles on solid-supportFull Text via DOI: 10.1016/S0040-4039(03)01219-X Web of Science: 000183780300037
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2003Solid-phase synthesis of new fused tetra, penta and hexacyclic beta-carboline derivativesFull Text via DOI: 10.1016/S0040-4039(03)00181-3 Web of Science: 000181242600052
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2002Opioid activity of 4-imidazolidinone positional analogues of Leu-enkephalinFull Text via DOI: 10.1016/S0960-894X(02)00678-9 Web of Science: 000178693100034
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2002Parallel solid-phase synthesis of disubstituted 1,6-piperazine-2-onesFull Text via DOI: 10.1021/cc0200235 Web of Science: 000179254700002
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2002An expedient method for the solid-phase synthesis of alpha-aminoalkyl phosphonopeptidesFull Text via DOI: 10.1016/S0040-4039(02)00695-0 Web of Science: 000175894400034
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2002Solid-phase synthesis of 1,2,5-trisubstituted 4-imidazolidinonesFull Text via DOI: 10.1021/cc0100565 Web of Science: 000175658100006
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2002An efficient approach for solid-phase synthesis of peptidomimetics based on 4-imidazolidinonesFull Text via DOI: 10.1016/S0040-4039(02)00263-0 Web of Science: 000174765600006
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2002Solid-phase synthesis of linear ureas tethered to hydantoins and thiohydantoinsFull Text via DOI: 10.1021/cc010064l Web of Science: 000174633500013
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2001Solid-phase synthesis of alpha,alpha-difluoro-beta-amino acids via the Reformatsky reactionFull Text via DOI: 10.1021/jo010872z Web of Science: 000172489500053
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2001Parallel synthesis of 4,5-dihydro-1H-1,4-benzodiazepine-2,3-dionesFull Text via DOI: 10.1016/S0040-4039(01)00939-X Web of Science: 000170062400003
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2001Tethered libraries: Solid-phase synthesis of substituted urea-linked bicyclic guanidinesFull Text via DOI: 10.1021/cc0000803 Web of Science: 000169606600009
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2001Solid-phase synthesis of bis-heterocyclic compounds from resin-bound orthogonally protected lysineFull Text via DOI: 10.1021/cc000061t Web of Science: 000167935000010
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2000Solid-phase synthesis of bis-2-imidazolidinethiones from resin-bound tripeptidesFull Text via DOI: 10.1021/ol000225e Web of Science: 000089831900026
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2000An efficient two-step synthesis of mono-, di- and triureas from resin-bound amidesFull Text via DOI: 10.1016/S0040-4039(00)00845-5 Web of Science: 000088200200003
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2000Solid-phase synthesis of substituted 2,3-diketopiperazines from reduced polyamidesFull Text via DOI: 10.1016/S0040-4020(00)00253-2 Web of Science: 000087032100006
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2000Solid phase synthesis of 1-substituted pyroglutamatesFull Text via DOI: 10.1016/S0040-4039(99)02208-X Web of Science: 000085305600017
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2000Solid phase synthesis of 1,3-disubstituted succinimidesFull Text via DOI: 10.1016/S0040-4039(99)02166-8 Web of Science: 000085038700008
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1999Solid phase synthesis of 1,4-benzothiazepin-5-one derivativesFull Text via DOI: 10.1016/S0040-4039(99)00964-8 Web of Science: 000081122400006
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1999Solid-Phase Synthesis of trisubstituted 2-imidazolidones and 2-imidazolidinethionesFull Text via DOI: 10.1021/cc980019m Web of Science: 000081948200005
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1998Efficient solid phase synthesis of 3,5-disubstituted hydantoinsFull Text via DOI: 10.1016/S0040-4039(98)01874-7 Web of Science: 000076524100004
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1998Combinatorial chemistry: From peptides and peptidomimetics to small organic and heterocyclic compoundsFull Text via DOI: 10.1016/S0960-894X(98)00412-0 Web of Science: 000075976300002
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1998Solid phase synthesis of 2,4,5-trisubstituted thiomorpholin-3-onesFull Text via DOI: 10.1016/S0040-4039(98)00645-5 Web of Science: 000073724300014
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1997Solid phase synthesis of 1,3,4,7-tetrasubstituted perhydro-1,4-diazepine-2,5-dionesFull Text via DOI: 10.1016/S0040-4039(97)01086-1 Web of Science: A1997XK06100007
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1997Solid phase synthesis of heterocyclic compounds from linear peptides: Cyclic ureas and thioureasFull Text via DOI: 10.1016/S0040-4039(96)02516-6 Web of Science: A1997WG34800010
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1996Pseudo-prolines as a solubilizing, structure-disrupting protection technique in peptide synthesisFull Text via DOI: 10.1021/ja961509q Web of Science: A1996VK78000002
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1995
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1995CHEMOSELECTIVE LIGATION OF MULTIFUNCTIONAL PEPTIDES TO TOPOLOGICAL TEMPLATES VIA THIOETHER FORMATION FOR TASP SYNTHESISFull Text via DOI: 10.1016/0040-4039(94)02230-9 Web of Science: A1995QA28200011
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Book Chapter
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2002Synthesis of cyclic ureas and cyclic thioureas from acyl dipeptides. 264-266.Full Text via DOI: 10.1007/0-306-46862-x_109
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2001Solid Phase Synthesis of 1,2,5-Substituted Derivatives of 4-Imidazolidinone. 257-258.Full Text via DOI: 10.1007/978-94-010-0464-0_116
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2001Solid-Phase Synthesis of Substituted Dihydroimidazoles and Their Bis Analogs. 255-256.Full Text via DOI: 10.1007/978-94-010-0464-0_115
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2001Solid-Phase Synthesis of α-Difluoro-β-amino Acids by a Reformatsky Reaction. 261-262.Full Text via DOI: 10.1007/978-94-010-0464-0_118
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2000
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2000Solid phase synthesis of heterocyclic combinatorial libraries derived from peptides. 192-197.Web of Science: 000166933900049
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1999
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1999Preparation of heterocyclic positional scanning combinatorial libraries from peptides. 123-127.Web of Science: 000081131800040
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Conference
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2010
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2005Solid-phase synthesis of triazinobenzimidazole libraries. U3443-U3444.Web of Science: 000236797306695
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2004Efficient synthesis of fused tetracyclic benzimidazole systems. 39-40.Web of Science: 000238911100013
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2004Parallel solid-phase synthesis of difluorinated dipeptide analogs. 63-64.Web of Science: 000238911100025
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2003Solid-phase synthesis of alpha,alpha-difluorinated beta-amino acids by Reformatsky reaction. 353-353.Web of Science: 000183878800350
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2003
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2002Solid phase synthesis of alpha,alpha-difluoro-beta-amino acid derivatives by Reformatsky reaction.. U556-U556.Web of Science: 000176296703054
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2002Solid phase synthesis of alpha,alpha-difluoro-beta-amino acid derivatives by reformatsky reaction.. B209-B209.Web of Science: 000176296801157
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1999Synthesis of cyclic ureas and cyclic thioureas from acyl dipeptides. 265-266.Web of Science: 000085202200109
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Letter
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1998Solid-phase synthesis of trisubstituted bicyclic guanidines via cyclization of reduced N-acylated dipeptides. 8622-8623.Full Text via DOI: 10.1021/jo9810617 Web of Science: 000077376200001
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Other Scholarly Work
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2004Combinatorial chemistry: Libraries from libraries, the art of the diversity-oriented transformation of resin-bound peptides and chiral polyamides to low molecular weight acyclic and heterocyclic compounds. (vol 69,3603, 2004). 5516-5516.Full Text via DOI: 10.1021/jo040002s Web of Science: 000223008100057
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1999Mixture-based synthetic combinatorial libraries. 3743-3778.Full Text via DOI: 10.1021/jm990174v Web of Science: 000082783200001
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Review
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2011Synthesis of functionalized tetrasubstituted pyrazolyl heterocycles - A review. 5258-5275.Full Text via DOI: 10.1016/j.ejmech.2011.09.016 Web of Science: 000298120500003
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2010Recent methodologies toward the synthesis of valdecoxib: A potential 3,4-diarylisoxazolyl COX-II inhibitor. 4697-4707.Full Text via DOI: 10.1016/j.ejmech.2010.07.045 Web of Science: 000283911300001
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1997The current status of heterocyclic combinatorial libraries. 449-472.Full Text via DOI: 10.1021/cr960010b Web of Science: A1997WR43100006
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Research
principal investigator on
- Synthesis and screening of small molecule compounds for the discovery of new analgesics awarded by Alzheimer's and Aging Research Center 2021 - 2023
- Synthesis and in vitro and in vivo screening of fused and tethered heterocyclic peptidomimetics for the discovery of new analgesics with decreased side effects awarded by National Institute on Drug Abuse 2020 - 2022
- High throughput screening for anti-adhesion drugs against placental and cerebral malaria awarded by Allergy and Infectious Diseases 2020 - 2022
- Novel ROR gamma antagonists for inflammation and autoimmune disease awarded by Allergy and Infectious Diseases 2020 - 2022
Contact
full name
- Adel Nefzi
Identifiers
ORCID iD
- https://orcid.org/0000-0002-6332-5780 (confirmed)