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Nouri Neamati - One of the best experts on this subject based on the ideXlab platform.
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design and synthesis of novel pyrimidone analogues as hiv 1 Integrase Inhibitors
Bioorganic & Medicinal Chemistry Letters, 2013Co-Authors: Shenghui Yu, Nouri Neamati, Tino W. Sanchez, Guisen ZhaoAbstract:Abstract A series of novel pyrimidone analogues have been designed and synthesized as HIV-1 Integrase (IN) Inhibitors. This study demonstrated that introducing a substituent in the N1-position of the pyrimidone scaffold does not significantly influence IN inhibitory activity. Molecular docking studies showed these compounds could occupy the IN active site and form pi–pi interactions with viral DNA nucleotides DC16 and DA17 to displace reactive viral DNA 3′OH and block intasome activity.
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Synthesis, biological evaluation and 3D-QSAR studies of 3-keto salicylic acid chalcones and related amides as novel HIV-1 Integrase Inhibitors.
Bioorganic & medicinal chemistry, 2011Co-Authors: Horrick Sharma, Nouri Neamati, Shivaputra A. Patil, Tino W. Sanchez, Raymond F. Schinazi, John K. BuolamwiniAbstract:Abstract HIV-1 Integrase is one of the three most important enzymes required for viral replication and is therefore an attractive target for anti retroviral therapy. We herein report the design and synthesis of 3-keto salicylic acid chalcone derivatives as novel HIV-1 Integrase Inhibitors. The most active compound, 5-bromo-2-hydroxy-3-[3-(2,3,6-trichlorophenyl)acryloyl]benzoic acid ( 25 ) was selectively active against Integrase strand transfer, with an IC 50 of 3.7 μM. While most of the compounds exhibited strand transfer selectivity, a few were nonselective, such as 5-bromo-3-[3-(4-bromophenyl)acryloyl]-2-hydroxybenzoic acid ( 15 ), which was active against both 3′-processing and strand transfer with IC 50 values of 11 ± 4 and 5 ± 2 μM, respectively. The compounds also inhibited HIV replication with potencies comparable with their Integrase inhibitory potencies. Thus, 5-bromo-2-hydroxy-3-[3-(2,3,6-trichlorophenyl)acryloyl]benzoic acid ( 25 ) and 5-bromo-3-[3-(4-bromophenyl)acryloyl]-2-hydroxybenzoic acid ( 15 ) inhibited HIV-1 replication with EC 50 values of 7.3 and 8.7 μM, respectively. A PHASE pharmacophore hypothesis was developed and validated by 3D-QSAR, which gave a predictive r 2 of 0.57 for an external test set of ten compounds. Phamacophore derived molecular alignments were used for CoMFA and CoMSIA 3D-QSAR modeling. CoMSIA afforded the best model with q 2 and r 2 values of 0.54 and 0.94, respectively. This model predicted all the ten compounds of the test set within 0.56 log units of the actual pIC 50 values; and can be used to guide the rational design of more potent novel 3-keto salicylic acid Integrase Inhibitors
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hiv 1 Integrase Inhibitors 2007 2008 update
ChemInform, 2011Co-Authors: Kavya Ramkumar, Erik Serrao, Srinivas Odde, Nouri NeamatiAbstract:In recent years, HIV-1 Integrase (IN) has become an attractive target for designing antiretroviral agents. The first IN inhibitor approved for clinical use, raltegravir, has validated the pharmacological viability of IN Inhibitors and signals the advent of a new generation of antiretroviral drugs. The development of raltegravir and other successful lead IN Inhibitors has also influenced the IN inhibitor design strategy. This has led to the identification of several potent Inhibitors in these last two years. Further, an increased understanding of IN structural biology has opened up novel approaches to inhibiting IN, such as targeting its multimerization or interaction with cellular cofactors. This review covers recent developments in the field of IN inhibitor design from 2007 to 2008. © 2010 Wiley Periodicals, Inc. Med Res Rev, 30, No. 6, 890–954, 2010
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Raltegravir, elvitegravir, and metoogravir: the birth of "me-too" HIV-1 Integrase Inhibitors
Retrovirology, 2009Co-Authors: Erik Serrao, Kavya Ramkumar, Srinivas Odde, Nouri NeamatiAbstract:Merck's MK-0518, known as raltegravir, has recently become the first FDA-approved HIV-1 Integrase (IN) inhibitor and has since risen to blockbuster drug status. Much research has in turn been conducted over the last few years aimed at recreating but optimizing the compound's interactions with the protein. Resulting me-too drugs have shown favorable pharmacokinetic properties and appear drug-like but, as expected, most have a highly similar interaction with IN to that of raltegravir. We propose that, based upon conclusions drawn from our docking studies illustrated herein, most of these me-too MK-0518 analogues may experience a low success rate against raltegravir-resistant HIV strains. As HIV has a very high mutational competence, the development of drugs with new mechanisms of inhibitory action and/or new active substituents may be a more successful route to take in the development of second- and third-generation IN Inhibitors.
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anti infectives clinical progress of hiv 1 Integrase Inhibitors
Expert Opinion on Emerging Drugs, 2008Co-Authors: Laith Q Almawsawi, Rasha I Alsafi, Nouri NeamatiAbstract:Background: HIV-1 Integrase (IN) represents a therapeutically advantageous viral target to treat HIV/AIDS in the clinic. Over a decade of progress in the field has resulted in IN inhibitor chemical classes that display specificity for strand transfer catalysis of the enzyme, thus blocking viral DNA integration into host cell nuclear DNA, an essential step for viral infectivity. Objective: In this manuscript we provide an update on recent HIV-1 IN Inhibitors that have been clinically evaluated, which include MK-0518, MK-2048, GS-9137, GS-9160, GS-9224, GSK-364735, and BMS-707035. The information presented here can aid in the IN drug developmental process. Methods: We have limited the scope of this review to information available on the clinical evaluation of promising strand transfer-specific IN Inhibitors and their potential drug–drug interaction profiles with other antiretroviral agents. Results/conclusion: The development of strand transfer-specific inhibitor classes is an important achievement for the ...
Yves Pommier - One of the best experts on this subject based on the ideXlab platform.
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selectivity for strand transfer over 3 processing and susceptibility to clinical resistance of hiv 1 Integrase Inhibitors are driven by key enzyme dna interactions in the active site
Nucleic Acids Research, 2016Co-Authors: Mathieu Metifiot, Christophe Marchand, Terrence R Burke, Xue Zhi Zhao, Barry C Johnson, Evgeny Kiselev, Laura Marler, Stephen H Hughes, Yves PommierAbstract:: Integrase strand transfer Inhibitors (INSTIs) are highly effective against HIV infections. Co-crystal structures of the prototype foamy virus intasome have shown that all three FDA-approved drugs, raltegravir (RAL), elvitegravir and dolutegravir (DTG), act as interfacial Inhibitors during the strand transfer (ST) integration step. However, these structures give only a partial sense for the limited inhibition of the 3'-processing reaction by INSTIs and how INSTIs can be modified to overcome drug resistance, notably against the G140S-Q148H double mutation. Based on biochemical experiments with modified oligonucleotides, we demonstrate that both the viral DNA +1 and -1 bases, which flank the 3'-processing site, play a critical role for 3'-processing efficiency and inhibition by RAL and DTG. In addition, the G140S-Q148H (SH) mutant Integrase, which has a reduced 3'-processing activity, becomes more active and more resistant to inhibition of 3'-processing by RAL and DTG in the absence of the -1 and +1 bases. Molecular modeling of HIV-1 Integrase, together with biochemical data, indicate that the conserved residue Q146 in the flexible loop of HIV-1 Integrase is critical for productive viral DNA binding through specific contacts with the virus DNA ends in the 3'-processing and ST reactions. The potency of Integrase Inhibitors against 3'-processing and their ability to overcome resistance is discussed.
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probing chelation motifs in hiv Integrase Inhibitors
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Arpita Agrawal, Yves Pommier, Kasthuraiah Maddali, Jamie Desoto, Jessica L Fullagar, Shahrzad Rostami, Douglas D Richman, Seth M CohenAbstract:A series of HIV Integrase (HIV-1 IN) Inhibitors were synthesized to evaluate the role of the metal-binding group (MBG) in this class of metalloenzyme Inhibitors. A total of 21 different raltegravir-chelator derivative (RCD) compounds were prepared that differed only in the nature of the MBG. These IN strand-transfer Inhibitors (INSTIs) were evaluated in vitro in cell-free enzyme activity assays, and the in vitro results were further validated in cell culture experiments. All of the active compounds showed selective inhibition of the strand-transfer reaction over 3′-processing, suggesting a common mode of action with raltegravir. The results of the in vitro activity suggest that the nature of the MBG donor atoms, the overall MBG structure, and the specific arrangement of the MBG donor atom triad are essential for obtaining maximal HIV-1 IN inhibition. At least two compounds (RCD-4, RCD-5) containing a hydroxypyrone MBG were found to display superior strand-transfer inhibition when compared to an abbreviated analogue of raltegravir (RCD-1). By isolating and examining the role of the MBG in a series of INSTIs, we have identified a scaffold (hydroxypyrones) that may provide access to a unique class of HIV-1 IN Inhibitors, and may help overcome rising raltegravir resistance.
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evaluation of hiv 1 Integrase Inhibitors on human primary macrophages using a luciferase based single cycle phenotypic assay
Journal of Virological Methods, 2010Co-Authors: Zuleika Michelini, Roberta Costi, Roberto Di Santo, Roberta Amici, Clementina Maria Galluzzo, Donatella R M Negri, Pasqualina Leone, Roberta Bona, Vincenzo Summa, Yves PommierAbstract:Macrophages represent an important site for productive infection of HIV-1 and the evaluation of Integrase (IN) Inhibitors on this cell subset is of fundamental importance. In this report, preclinical evaluation of IN Inhibitors on primary human macrophages was attempted successfully using a 96-well microtiter phenotypic assay developed recently for the evaluation of IN Inhibitors in a cell-based system by taking advantage of HIV-derived lentiviral vectors expressing luciferase. IN Inhibitors were also tested using a lentiviral vector containing an IN with introduced T66I/S153Y mutations, known to affect the activity of azido-group-containing diketo acid (DKA) IN Inhibitors. Utilizing different classes of HIV Integrase Inhibitors against the wild-type IN and the mutant mentioned above, some of the IN Inhibitors used were also active on this particular mutant, suggesting that should HIV-1 develop additional or different mutations to become resistant to such anti-IN drugs, new drugs can be developed with a better resistance profile. This assay provides a standardized method for the preclinical evaluation of the efficacy of IN Inhibitors on wild-type and mutated IN that can be adapted easily for the evaluation of anti-IN activity on IN sequences derived from patients.
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resistance to Integrase Inhibitors
Viruses, 2010Co-Authors: Mathieu Metifiot, Christophe Marchand, Kasthuraiah Maddali, Yves PommierAbstract:Integrase (IN) is a clinically validated target for the treatment of human immunodeficiency virus infections and raltegravir exhibits remarkable clinical activity. The next most advanced IN inhibitor is elvitegravir. However, mutant viruses lead to treatment failure and mutations within the IN coding sequence appear to confer cross-resistance. The characterization of those mutations is critical for the development of second generation IN Inhibitors to overcome resistance. This review focuses on IN resistance based on structural and biochemical data, and on the role of the IN flexible loop i.e., between residues G140-G149 in drug action and resistance.
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diketoacid genre hiv 1 Integrase Inhibitors containing enantiomeric arylamide functionality
Bioorganic & Medicinal Chemistry, 2009Co-Authors: Xue Zhi Zhao, Christophe Marchand, Yves Pommier, Kasthuraiah Maddali, Terrence R BurkeAbstract:Using our recently disclosed 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one and 4,5-dihydroxy-1H-isoindole-1,3(2H)-dione Integrase Inhibitors, we report differential effects on inhibitory potency induced by introduction of an α-chiral center into a key aryl substituent. We show that introduction of the chiral center is uniformly deleterious to binding, with the (R)-enantiomer being more deleterious than the (S)-enantiomer. A greater enantiomeric difference in potency is shown by Inhibitors that have restricted rotation of the aryl ring, with the larger difference being due to poorer potency of the (R)-enantiomer rather than higher potency of the (S)-enantiomer. The potency difference for enantiomers based on the isoindoline-1,3-dione ring system is less than for those derived from the isoindol-1-one ring system. Our findings provide useful information that should aid in understanding molecular binding interactions of DKA-derived IN Inhibitors.
Masahiro Fuji - One of the best experts on this subject based on the ideXlab platform.
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Carbamoyl Pyridone HIV-1 Integrase Inhibitors 3. A Diastereomeric Approach to Chiral Nonracemic Tricyclic Ring Systems and the Discovery of Dolutegravir (S/GSK1349572) and (S/GSK1265744)
Journal of medicinal chemistry, 2013Co-Authors: Brian A Johns, Takashi Kawasuji, Teruhiko Taishi, David Temelkoff, Hiroshi Yoshida, Akiyama Toshiyuki, Yoshiyuki Taoda, Hitoshi Murai, Ryuichi Kiyama, Masahiro FujiAbstract:We report herein the discovery of the human immunodeficiency virus type-1 (HIV-1) Integrase Inhibitors dolutegravir (S/GSK1349572) (3) and S/GSK1265744 (4). These drugs stem from a series of carbamoyl pyridone analogues designed using a two-metal chelation model of the Integrase catalytic active site. Structure-activity studies evolved a tricyclic series of carbamoyl pyridines that demonstrated properties indicative of once-daily dosing and superior potency against resistant viral strains. An inherent hemiaminal ring fusion stereocenter within the tricyclic carbamoyl pyridone scaffold led to a critical substrate controlled diastereoselective synthetic strategy whereby chiral information from small readily available amino alcohols was employed to control relative and absolute stereochemistry of the final drug candidates. Modest to extremely high levels of stereochemical control were observed depending on ring size and position of the stereocenter. This approach resulted in the discovery of 3 and 4, which are currently in clinical development.
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carbamoyl pyridone hiv 1 Integrase Inhibitors 3 a diastereomeric approach to chiral nonracemic tricyclic ring systems and the discovery of dolutegravir s gsk1349572 and s gsk1265744
Journal of Medicinal Chemistry, 2013Co-Authors: Brian A Johns, Takashi Kawasuji, Teruhiko Taishi, David Temelkoff, Hiroshi Yoshida, Yoshiyuki Taoda, Hitoshi Murai, Ryuichi Kiyama, Toshiyuki Akiyama, Masahiro FujiAbstract:We report herein the discovery of the human immunodeficiency virus type-1 (HIV-1) Integrase Inhibitors dolutegravir (S/GSK1349572) (3) and S/GSK1265744 (4). These drugs stem from a series of carbamoyl pyridone analogues designed using a two-metal chelation model of the Integrase catalytic active site. Structure–activity studies evolved a tricyclic series of carbamoyl pyridines that demonstrated properties indicative of once-daily dosing and superior potency against resistant viral strains. An inherent hemiaminal ring fusion stereocenter within the tricyclic carbamoyl pyridone scaffold led to a critical substrate controlled diastereoselective synthetic strategy whereby chiral information from small readily available amino alcohols was employed to control relative and absolute stereochemistry of the final drug candidates. Modest to extremely high levels of stereochemical control were observed depending on ring size and position of the stereocenter. This approach resulted in the discovery of 3 and 4, which a...
Brian A Johns - One of the best experts on this subject based on the ideXlab platform.
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pyridopyrimidinone Inhibitors of hiv 1 rnase h
European Journal of Medicinal Chemistry, 2014Co-Authors: Emile Johann Velthuisen, Brian A Johns, Peter Gerondelis, Yan Chen, Ke Mou, Wenwen Zhang, John W Seal, Kendra E Hightower, Sonia R Miranda, Kevin K BrownAbstract:Using a structure based pharmacophore design, a weak inhibitor of RNase H, identified from a small library of two metal binding HIV-1 Integrase Inhibitors, was optimized for potency and physicochemical properties. This manuscript describes the SAR and in vivo DMPK for the pyridopyrimidinone class of Inhibitors.
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Carbamoyl Pyridone HIV-1 Integrase Inhibitors 3. A Diastereomeric Approach to Chiral Nonracemic Tricyclic Ring Systems and the Discovery of Dolutegravir (S/GSK1349572) and (S/GSK1265744)
Journal of medicinal chemistry, 2013Co-Authors: Brian A Johns, Takashi Kawasuji, Teruhiko Taishi, David Temelkoff, Hiroshi Yoshida, Akiyama Toshiyuki, Yoshiyuki Taoda, Hitoshi Murai, Ryuichi Kiyama, Masahiro FujiAbstract:We report herein the discovery of the human immunodeficiency virus type-1 (HIV-1) Integrase Inhibitors dolutegravir (S/GSK1349572) (3) and S/GSK1265744 (4). These drugs stem from a series of carbamoyl pyridone analogues designed using a two-metal chelation model of the Integrase catalytic active site. Structure-activity studies evolved a tricyclic series of carbamoyl pyridines that demonstrated properties indicative of once-daily dosing and superior potency against resistant viral strains. An inherent hemiaminal ring fusion stereocenter within the tricyclic carbamoyl pyridone scaffold led to a critical substrate controlled diastereoselective synthetic strategy whereby chiral information from small readily available amino alcohols was employed to control relative and absolute stereochemistry of the final drug candidates. Modest to extremely high levels of stereochemical control were observed depending on ring size and position of the stereocenter. This approach resulted in the discovery of 3 and 4, which are currently in clinical development.
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carbamoyl pyridone hiv 1 Integrase Inhibitors 3 a diastereomeric approach to chiral nonracemic tricyclic ring systems and the discovery of dolutegravir s gsk1349572 and s gsk1265744
Journal of Medicinal Chemistry, 2013Co-Authors: Brian A Johns, Takashi Kawasuji, Teruhiko Taishi, David Temelkoff, Hiroshi Yoshida, Yoshiyuki Taoda, Hitoshi Murai, Ryuichi Kiyama, Toshiyuki Akiyama, Masahiro FujiAbstract:We report herein the discovery of the human immunodeficiency virus type-1 (HIV-1) Integrase Inhibitors dolutegravir (S/GSK1349572) (3) and S/GSK1265744 (4). These drugs stem from a series of carbamoyl pyridone analogues designed using a two-metal chelation model of the Integrase catalytic active site. Structure–activity studies evolved a tricyclic series of carbamoyl pyridines that demonstrated properties indicative of once-daily dosing and superior potency against resistant viral strains. An inherent hemiaminal ring fusion stereocenter within the tricyclic carbamoyl pyridone scaffold led to a critical substrate controlled diastereoselective synthetic strategy whereby chiral information from small readily available amino alcohols was employed to control relative and absolute stereochemistry of the final drug candidates. Modest to extremely high levels of stereochemical control were observed depending on ring size and position of the stereocenter. This approach resulted in the discovery of 3 and 4, which a...
Myriam Witvrouw - One of the best experts on this subject based on the ideXlab platform.
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exploration of novel thiobarbituric acid rhodanine and thiohydantoin based hiv 1 Integrase Inhibitors
Bioorganic & Medicinal Chemistry Letters, 2009Co-Authors: Suvi Rajamaki, Cristina Tintori, Myriam Witvrouw, Frauke Christ, Zeger Debyser, Anna Innitzer, Chiara Falciani, S Massa, Maurizio BottaAbstract:A novel compound inhibiting HIV-1 Integrase has been identified by means of virtual screening techniques. A small family of structurally related molecules has been synthesized and biologically evaluated with some of the compounds possessing micromolar activity both in enzymatic and cellular assays.
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synthesis and antiviral properties of some polyphenols related to salvia genus
Bioorganic & Medicinal Chemistry Letters, 2008Co-Authors: Clemence Queffelec, Myriam Witvrouw, Jeanfrancois Mouscadet, Fabrice Bailly, Gladys Mbemba, Sean Hayes, Zeger Debyser, Philippe CotelleAbstract:An efficient synthesis of the acid part of salvianolic acid E 2 is described. Compound 2 was obtained from vanillin in 10 steps and 21% overall yield. During the synthesis of 2 an unexpected 5-oxo-4b,9b-dihydroindano[1,2-b]benzofuran rac-12 was isolated. Both compounds together with the acid part of salvianolic acid D were active as HIV-1 Integrase Inhibitors at the submicromolar level. But they did not inhibit the replication of the virus on MT-4 cells.
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investigations on the 4 quinolone 3 carboxylic acid motif 1 synthesis and structure activity relationship of a class of human immunodeficiency virus type 1 Integrase Inhibitors
Journal of Medicinal Chemistry, 2008Co-Authors: Serena Pasquini, Claudia Mugnaini, Cristina Tintori, Maurizio Botta, Alejandro Trejos, Riina K Arvela, Mats Larhed, Myriam Witvrouw, Martine Michiels, Frauke ChristAbstract:A set of 4-quinolone-3-carboxylic acids bearing different substituents on the condensed benzene ring was designed and synthesized as potential HIV-1 Integrase Inhibitors structurally related to elvitegravir. Some of the new compounds proved to be able to inhibit the strand transfer step of the virus integration process in the micromolar range. Docking studies and quantum mechanics calculations were used to rationalize these data.
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quinolone 3 carboxylic acid pharmacophore design of second generation hiv 1 Integrase Inhibitors
Journal of Medicinal Chemistry, 2008Co-Authors: Raveendra Dayam, Myriam Witvrouw, Laith Q Almawsawi, Zeger Debyser, Zahrah Zawahir, Nouri NeamatiAbstract:Two decades of intensive research efforts have led to the discovery of a large number of HIV-1 Integrase (IN) Inhibitors. Recently, the United States Food and Drug Administration (US FDA) approved MK-0518, or raltegravir (1), as the first IN inhibitor for HIV/AIDS treatment. Growing clinical evidence also demonstrates that the emergence of HIV-1 virus strains bearing IN amino acid substitutions that confer resistance to IN Inhibitors is inevitable. The discovery of second generation Inhibitors with potency against viral strains bearing drug resistant IN substitutions is necessary for ongoing effective treatment of viral infections. We generated common feature pharmacophore hypotheses using a training set of quinolone 3-carboxylic acid IN Inhibitors, including the clinical candidate GS-9137 (2). A database search of small molecules using the quinolone 3-carboxylic acid pharmacophore model, followed by in vitro evaluation of selected hits in an assay specific to IN, resulted in the discovery of potential le...
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Chicoric acid analogues as HIV-1 Integrase Inhibitors.
Journal of medicinal chemistry, 1999Co-Authors: Zhaiwei Lin, Nouri Neamati, Myriam Witvrouw, He Zhao, Yoshimitsu Kiryu, Jim A. Turpin, Claudia Aberham, Klaus Strebel, Kurt W. Kohn, Christophe PannecouqueAbstract:The present study was undertaken to examine structural features of l-chicoric acid (3) which are important for potency against purified HIV-1 Integrase and for reported cytoprotective effects in ce...