L-chicoric Acid Research Articles

An Emerging Class of Antimicrobial Heterocycles Derived from Natural Sources

: An energetic desire to reduce the undesirable effects brought on by synthetic heterocyclic substances and to combat antimicrobial resistance has led to an increase in curiosity in using natural antimicrobial agents derived from plants, such as phenolics, catechol, pyrogallol, essential oils, Lchicoric acid, caffeic acid, catechins, coumarin, proanthocyanidins, 4-thiazolidinone, and alkaloids. The usage of naturally occurring heterocycles against Gram-positive (S. aureus, S. pyogenes, B. subtilis, A. niger, and B. cereus) and Gram-negative (P. aeruginosa, E. coli, K. pneumonia, P. vulgaris, and S. infantis) bacteria has been the subject of increased investigation in past few decades. This review targets the use of plant-derived antimicrobials to increase the microbiological safety of food and the possible antimicrobial activity of nitrogen- and oxygen-based heterocyclic compounds. It is possible to find novel medications to treat infectious diseases and address the issues brought on by antibiotic resistance by exploring and utilising the potential of these chemicals. Additional research is desirable on the toxicological effects and potential additive and/or synergistic antimicrobial actions in order to maximise the usage of these potential natural antimicrobials in foods.

Discovery and structural characterization of chicoric acid as a SARS-CoV-2 nucleocapsid protein ligand and RNA binding disruptor

The nucleocapsid (N) protein plays critical roles in coronavirus genome transcription and packaging, representing a key target for the development of novel antivirals, and for which structural information on ligand binding is scarce. We used a novel fluorescence polarization assay to identify small molecules that disrupt the binding of the N protein to a target RNA derived from the SARS-CoV-2 genome packaging signal. Several phenolic compounds, including L-chicoric acid (CA), were identified as high-affinity N-protein ligands. The binding of CA to the N protein was confirmed by isothermal titration calorimetry, 1H-STD and 15N-HSQC NMR, and by the crystal structure of CA bound to the N protein C-terminal domain (CTD), further revealing a new modulatory site in the SARS-CoV-2 N protein. Moreover, CA reduced SARS-CoV-2 replication in cell cultures. These data thus open venues for the development of new antivirals targeting the N protein, an essential and yet underexplored coronavirus target.

The composition and vascular/antioxidant properties of Taraxacum officinale flower water syrup in a normal-fat diet using an obese rat model

Ethnopharmacological relevanceTaraxacum officinale (L.), commonly called dandelion has been used for centuries as a natural medicine to treat inflammatory diseases including some metabolic alterations associated with obesity. Aim of the studyBased on animal experiments this study aims to explore the potential mechanisms of action of T. officinale flower water syrup (TOFS) together with a normal-fat diet in the intervention of obesity. Materials and methodsObese male albino-Wistar rats (n = 8) at 25 weeks of age were fed with a normal-fat diet with or without added 27.82% TOFS (w/w) for 4 weeks. The reactivity of thoracic aorta and antioxidant capacity were studied. ResultsTOFS delivered daily 926.8 μg of L-chicoric acid, 20.19 μg of luteolin and 3.379 ‬g of sucrose. TOFS showed beneficial effects by regulating blood lipids (HDL, x1.11-fold increase), thereby lowering the risk factors for atherosclerosis (TC/HDL, x0.90-fold). The antioxidant status was improved via an increase in plasma superoxide radical scavenging (SOD, x1.6-fold) and a decrease in lipid peroxidation (MDA, x0.81-fold). Moreover, the following were decreased: Cu (x0.53-fold), Zn (x0.72-fold) and the Cu/Zn molar ratio (x0.60-fold). A marker for liver damage/disease was beneficially decreased (ALP, x0.87-fold). TOFS modulated in a significant way COX-depended relaxation to ACh (p = 0.05) but not to CORM-2 (p = 0.1651) in isolated thoracic arteries, by decreased participation of vasoconstrictor prostanoids. The vascular contraction to prostaglandin F2α was also decreased (x0.62-fold). We observed no change in the feed intake, body weight, organ-to-body weight ratio, blood glucose, CAT, FRAP, AST, ALT, TBARS/carbonyls (in heart, liver, kidneys, spleen) and carbonyls (in blood plasma, thoracic arteries); as well as F2-isoprostanes in urine. Vascular response to the vasodilators ACh, SNP, A23187, CORM-2, pinacidil, NS-1619 and to the vasoconstrictors NA, U-46619, ET-1 as well as hyperpolarizing mechanism(s) were not modified. ConclusionsTOFS possesses beneficial properties by regulating prostanoids and antioxidant status.

Phenolic Fractions from Dandelion Leaves and Petals as Modulators of the Antioxidant Status and Lipid Profile in an In Vivo Study.

Alcoholic leaf and petal fractions of Taraxacum officinale (dandelion) were previously demonstrated to exert in vitro antioxidant and antithrombotic activities in blood plasma and platelets. Eight-week-old male Wistar rats (n = 6) were supplemented for four weeks with dandelion fractions (694 mg/kg of diet = 11.9 ± 0.6 mg daily). Dandelion leaf and petal fractions, which delivered daily 4.10 ± 0.05 and 1.41 ± 0.07 mg l-chicoric acid, respectively, were shown to exert antioxidative actions, measured as decreased levels of thiobarbituric acid-reactive substances (TBARS) in the spleen (≈0.8-fold, leaves and petals), brain (0.53-fold, leaves) and thoracic arteries (0.59-fold, petals). Moreover, petal fraction increased thiols in the blood plasma (1.58-fold), while leaf fraction decreased protein carbonylation levels (0.59-fold). Additionally, dandelion leaf fractions modified the lipid profile: decreased triglyceride (0.44-fold), total cholesterol (0.73-fold), lipoprotein combine index (0.32-fold) and the atherogenic index of plasma (0.62-fold). Dandelion fractions showed a beneficial decrease effect in the participation of cyclooxygenase products in the noradrenaline-induced vascular contractions of thoracic arteries. Meanwhile, only the dandelion leaf fraction augmented acetylcholine-induced vasodilation and upregulated KATP channels. The heart rate and blood pressure were not modified. Dandelion leaf and petal phenolic fractions, enriched with l-chicoric acid, are promising plant materials that may exert in vivo beneficial antioxidant effects.

The anti-oxidative and hemostasis-related multifunctionality of L-chicoric acid, the main component of dandelion: An in vitro study of its cellular safety, antioxidant and anti-platelet properties, and effect on coagulation

Abstract All dandelion (Taraxacum officinale) organs, i.e. the roots, leaves and flowers, are rich in L-chicoric acid, and nowadays are commonly included in dietary products and pharmaceutical preparations. However, little is known of the effects of dandelion leaves and petals, or L-chicoric acid itself, on the biological activity hemostasis elements such as blood platelets and plasma. Therefore, the aim of the present study was to examine the effect of chicoric acid extracted from dandelion on the biological properties of human plasma and blood platelets in vitro. Briefly, the study evaluated the effects of four phenolic fractions, obtained from leaves (fraction A and B) and petals (fraction C and D), with different concentrations of chicoric acid, as well as L-chicoric acid isolated from dandelion leaves, on biomarkers of oxidative stress, parameters of coagulation and blood platelet activation. Chicoric acid offers novel antioxidant and anti-adhesive potential without cytotoxicity.

Determination of Variance of Secondary Metabolites in Lettuces Grown Under Different Light Sources by Flow Injection Mass Spectrometric (FIMS) Fingerprinting and ANOVA–PCA

Lettuce (Lactuca sativa L.) is one of the most consumed vegetables in the world and different management practice can result in considerable variability of the secondary metabolites. Flow injection mass spectrometry (FIMS) combined with analysis of variance–principle component analysis (ANOVA–PCA) was used to study differences in the secondary metabolites originating from different lighting conditions (Sunlight, white light, and florescent light) and lettuce varieties (Romaine and Lollo Rossa). Ultra-high-performance liquid chromatography–high-resolution accurate mass spectrometry was used for putative marker compound identification. Quinic acid, caffeic acid, chlorogenic acid, L-chicoric acid, and quercetin malonyl glucoside varied significantly for Romaine lettuce grown under different light conditions. The study showed that the combination of FIMS fingerprinting and ANOVA–PCA can be a useful tool for the characterization of the sources of variance in plant materials regarding to genetic, environmental, and management factors.

Identification of fukinolic acid from Cimicifuga heracleifolia and its derivatives as novel antiviral compounds against enterovirus A71 infection

Human enterovirus 71 (EV-A71) infections cause a wide array of diseases ranging from diarrhoea and rashes to hand-foot-and-mouth disease and, in rare cases, severe neurological disorders. No specific antiviral drug therapy is currently available. Extracts from 75 Chinese medicinal plants selected for antiviral activity based on the Chinese pharmacopeia and advice from traditional Chinese medicine clinicians were tested for activity against EV-A71. The aqueous extract of the rhizome of Cimicifuga heracleifolia (Sheng Ma) and Arnebia euchroma (Zi Cao) showed potent antiviral activity. The active fractions were isolated by bioassay-guided purification, and identified by a combination of high-resolution mass spectrometry and nuclear magnetic resonance. Fukinolic acid and cimicifugic acid A and J, were identified as active anti-EV-A71 compounds for C. heracleifolia, whereas for A. euchroma, two caffeic acid derivatives were tentatively deduced. Commercially available fukinolic acid analogues such as L-chicoric acid and D-chicoric also showed in vitro micromolar activity against EV-A71 lab-strain and clinical isolates.

Increase in insulin sensitivity by the association of chicoric acid and chlorogenic acid contained in a natural chicoric acid extract (NCRAE) of chicory (Cichorium intybus L.) for an antidiabetic effect

Ethnopharmacological relevanceChicory (Cichorium intybus L.) is an indigenous vegetable widely cultivated in Europe, America and Asia. In ancient times, the leaves, flowers, seeds, and roots have been used as a wealth of health benefits including its tonic effects, the ability to ease digestive problems and to detoxify liver. In Indian traditional therapy, chicory was known to possess antidiabetic effect. In the traditional medicine of Bulgaria and Italy, chicory was used as hypoglycemic decoctions. Aims of the studiesWe wanted to obtain the complete chemical composition of the natural chicoric acid extract (NCRAE), a chicory root extract rich in chicoric acid, which previously showed its glucose tolerance effect in normal rats. To investigate if the whole NCRAE is required to be effective, we performed a comparative in vivo experiment on STZ diabetic rats treated either with NCRAE or a mixture composed of the two major compounds of NCRAE. Materials and methodsLC-MS method has been used to analyze the exhaustive composition of NCRAE: we have determined that chicoric acid and chlorogenic acid represented 83.8% of NCRAE. So, we have prepared a solution mixture of chicoric acid and chlorogenic acid named SCCAM, in order to compare in vivo the antidiabetic effects of this last and NCRAE in streptozotocin diabetic rats. In vitro experiments were performed on L6 cell line both for glucose uptake and for the protective effect against H2O2 oxidative stress. Also, we have evaluated DPPH and ORAC (Oxygen Radical Absorbance Capacity) antioxidative capacities of the two compositions. ResultsThe LC-MS analysis confirmed the high abundance of chicoric acid (64.2%) in NCRAE and a second part of NCRAE is composed of caffeoylquinic acids (CQAs) at 19.6% with among them the chlorogenic acid. This result has permitted us to prepare a mixture of synthetic L-chicoric acid (70%) and synthetic chlorogenic acid (30%): the solution is designated SCCAM. Our results showed that both NCRAE and SCCAM are able to improve a glucose tolerance in STZ diabetic rats after a subchronic administration of seven days. Alone NCRAE allows to significantly decrease the basal hyperglycemia after six days of treatment. To explain these difference of effects between NCRAE and SCCAM, we have compared their in vitro effects on the L6 muscle cell line both for the insulin sensitizing effect and for their protective action in pretreatment against H2O2. We have also compared their antioxidant capacities. In conclusion, we demonstrated that NCRAE, a natural extract of chicory (Cichorium intybus) rich in CRA and CQAs improves glucose tolerance and reduces the basal hyperglycemia in STZ diabetic rats.

Deciphering the influence of column chemistry and mass spectrometry settings for the analyses of geometrical isomers of L-chicoric acid.

Resolving the chemo-diversity of plant extract samples is an essential step for in-depth analyses of natural products which often exhibit promising biological activities. One of the challenges in this endeavor has been the confident differentiation of geometrical isomers. In this study, we investigated these aspects in chromatography (column chemistry and mobile phase composition) and mass spectrometry settings with regards to better differentiation of geometrical isomers. A standard of a hydroxycinnamic acid (HCA) derivative, L-chicoric acid (L-CA) - a di-acylated caffeoyltartaric acid ester found in a number of plant families - was used. Geometrical isomers of L-CA were formed by exposing the compound to ultraviolet (UV) radiation, to mimic the natural environment. The high performance liquid chromatography photo-diode array (HPLC-PDA) and ultra-high performance liquid chromatography mass spectrometry (UHPLC-MS) platforms were used to analyze the trans and cis geometrical isomers of L-CA. The HPLC-PDA results confirmed the generation of two cis geometrical isomers following UV exposure of the authentic trans-L-CA standard. Furthermore, the HPLC-PDA analyses demonstrated that the changes in both column chemistry (reverse-phase: C18, biphenyl, phenyl-hexyl and pentafluorophenyl propyl) and mobile phase composition (aqueous acetonitrile and aqueous methanol) affect the chromatographic elution profiles of the L-CA isomers. The MS results, on the other hand, revealed undisputed fragmentation differences between the geometrical isomers of L-CA. Thus, this study demonstrates that the identification of the L-CA isomers can be achieved more efficiently and confidently with good chromatography coupled to well-optimized mass spectrometry conditions, a requirement which has been proven impossible with other types of HCA derivatives. Moreover, differences in the binding modes of L-CA geometrical isomers to the HIV type 1 integrase enzyme were observed, suggesting a synergistic anti-HIV-1 activity of these isomers.

Mutagenesis of Lysines 156 and 159 in Human Immunodeficiency Virus Type 1 Integrase (IN) Reveals Differential Interactions between these Residues and Different IN Inhibitors

Human immunodeficiency virus (HIV) type I integrase (IN) active site, and viral DNA-binding residues K156 and K159 are predicted to interact both with strand transfer-selective IN inhibitors (STI), e.g. L-731,988, Elvitegravir (EVG), and the FDA-approved IN inhibitor, Raltegravir (RGV), and strand transfer non-selective inhibitors, e.g. dicaffeoyltartaric acids (DCTAs), e.g. L-chicoric acid (L-CA). To test posited roles for these two lysine residues in inhibitor action we assayed the potency of L-CA and several STI against a panel of K156 and K159 mutants. Mutagenesis of K156 conferred resistance to L-CA and mutagenesis of either K156 or K159 conferred resistance to STI indicating that the cationic charge at these two viral DNA-binding residues is important for inhibitor potency. IN K156N, a reported polymorphism associated with resistance to RGV, conferred resistance to L-CA and STI as well. To investigate the apparent preference L-CA exhibits for interactions with K156, we assayed the potency of several hybrid inhibitors containing combinations of DCTA and STI pharmacophores against recombinant IN K156A or K159A. Although K156A conferred resistance to diketo acid-branched bis-catechol hybrid inhibitors, neither K156A nor K159A conferred resistance to their monocatechol counterparts, suggesting that bis-catechol moieties direct DCTAs toward K156. In contrast, STI were more promiscuous in their interaction with K156 and K159. Taken together, the results of this study indicate that DCTAs interact with IN in a manner different than that of STI and suggest that DCTAs are an attractive candidate chemotype for development into drugs potent against STI-resistant IN.

Identification of chicoric acid as a hypoglycemic agent from Ocimum gratissimum leaf extract in a biomonitoring in vivo study

Ocimum gratissimum L. is popularly used to treat diabetes mellitus. The hypoglycemic activity of this medicinal species has been confirmed by in vivo studies. The present study conducted a chemical investigation of a leaf decoction (10% p/v) of O. gratissimum monitored by in vivo hypoglycemic activity assays. Four phenolic substances were identified: l-caftaric acid (1), l-chicoric acid (2), eugenyl-β-d-glucopyranoside (3) and vicenin-2 (4). The acute hypoglycemic activity of the O. gratissimum decoction fractions Og1-S (300mg/kg), Og1-A (240mg/kg) and Og1-B (80mg/kg) was evaluated intraperitoneally in normal and streptozotocin-induced diabetic mice. They reduced glycemia by 63%, 76% and 60% (in 120min), respectively, in the diabetic mice. Subfractions of Og1-A were also evaluated under the same conditions: Og1-AS (200mg/kg) and Og1-AP (40mg/kg) produced a decrease of only 37% and 39%, respectively. Among the major phenolic substances, only chicoric acid (2; 3mg/kg) reduced significantly the glycemic levels of diabetic mice by 53%, 120min after treatment. This is the first study describing the hypoglycemic activity of chicoric acid in an animal model of diabetes mellitus. In addition, we suggest that there may be other substances contributing to this activity. Thus, for the first time, a correlation is established between the hypoglycemic activity of O. gratissimum and its chemical composition.

Design, Synthesis, and Biological Evaluation of Novel Hybrid Dicaffeoyltartaric/Diketo Acid and Tetrazole-Substitutedl-Chicoric Acid Analogue Inhibitors of Human Immunodeficiency Virus Type 1 Integrase

Fourteen analogues of the anti-HIV-1 integrase (IN) inhibitor L-chicoric acid (L-CA) were prepared. Their IC(50) values for 3'-end processing and strand transfer against recombinant HIV-1 IN were determined in vitro, and their cell toxicities and EC(50) against HIV-1 were measured in cells (ex vivo). Compounds 1-6 are catechol/β-diketoacid hybrids, the majority of which exhibit submicromolar potency against 3'-end processing and strand transfer, though only with modest antiviral activities. Compounds 7-10 are L-CA/p-fluorobenzylpyrroloyl hybrids, several of which were more potent against strand transfer than 3'-end processing, a phenomenon previously attributed to the β-diketo acid pharmacophore. Compounds 11-14 are tetrazole bioisosteres of L-CA and its analogues, whose in vitro potencies were comparable to L-CA but with enhanced antiviral potency. The trihydroxyphenyl analogue 14 was 30-fold more potent than L-CA at relatively nontoxic concentrations. These data indicate that L-CA analogues are attractive candidates for development into clinically relevant inhibitors of HIV-1 IN.

A docking study of l-chicoric acid with HIV-1 integrase

Human immunodeficiency virus 1 integrase (HIV-1 IN) is the enzyme responsible for integrating the viral DNA into the host genome, and is essential to the replication of the virus. l-Chicoric acid (l-CA) is a bidentate catechol that has been identified as a potent inhibitor of HIV-1 IN. Using the new Autodock 4.0 free-energy function we have obtained a l-CA binding mode that explains its observed potency and is consistent with available experimental data. Because of the α,β-unsaturated ester functionality of the side arms of l-CA we first performed an extensive conformational analysis of l-CA using semiempirical and ab initio calculations. As a result we have identified two distinct l-CA binding modes, one for the s-cis/s-cis and another for the s-cis/s-trans isomers. The most stable conformer was found to be the structure with the α,β-unsaturated ester in the s-cis conformation for both arms of l-CA. This conformer also gave the top-ranked docking solution. Analysis of the interactions with key IN residues, combined with results using a l-CA tetraacetylated derivative and a Q148A IN mutant, correlate well with the experimental data.

Study on the drug resistance and the binding mode of HIV-1 integrase with LCA inhibitor

Human immunodeficiency virus type 1 (HIV-1) integrase (IN) is an essential enzyme in the lifecycle of this virus and also an important target for the study of anti-HIV drugs. The binding mode of the wild type IN core domain and its G140S mutant with L-Chicoric acid (LCA) inhibitor were investigated by using multiple conformation molecular docking and molecular dynamics (MD) simulation. Based on the binding modes, the drug resistance mechanism was explored for the G140S mutant of IN with LCA. The results indicate that the binding site of the G140S mutant of IN core domain with LCA is different from that of the core domain of the wild type IN, which leads to the partial loss of inhibition potency of LCA. The flexibility of the IN functional loop region and the interactions between Mg2+ ion and the three key residues (i.e., D64, D116, E152) stimulate the biological operation of IN. The drug resistance also lies in several other important effects, such as the repulsion between LCA and E152 in the G140S mutant core domain, the weakening of K159 binding with LCA and Y143 pointing to the pocket of the G140S mutant. All of the above simulation results agree well with experimental data, which provide us with some helpful information for designing the drug of anti-HIV based on the structure of IN.

Caffeoylglycolic and caffeoylamino acid derivatives, halfmers of l-chicoric acid, as new HIV-1 integrase inhibitors

Human immunodeficiency virus (HIV) integrase (IN) catalyzes the integration of HIV DNA copy into the host cell DNA. l-Chicoric acid ( 1) has been found to be one of the most potent HIV-1 integrase inhibitor. Caffeoylglycolic and caffeoylamino acid derivatives' halfmeric structures of l-chicoric acid 2 were synthesized for the purpose of simplifying the structure of l-chicoric acid. Among synthesized, compounds 2c and 3f showed HIV-1 IN inhibitory activities with IC 50 values of 10.5 and 12.0 μM, respectively, comparable to that of parent compound l-chicoric acid (IC 50 = 15.7 μM).

Cluster analysis and three-dimensional QSAR studies of HIV-1 integrase inhibitors

Three-dimensional quantitative structure-activity relationship (3D QSAR) and cluster analysis were applied to a variety of HIV-1 integrase inhibitors. One structure was chosen from each of 11 classes of inhibitors to represent the whole class in descriptor-based cluster analysis. The 11 classes of inhibitors were classified into two groups. The molecular field analysis (MFA) models for these two clusters had r 2 values of 0.90 and 0.95 and q 2 values of 0.85 and 0.91 that were noticeably enhanced from those of conventional QSAR models. The five test compounds, which were proposed to have a common binding site near the metal in HIV-1 integrase based on docking studies by Sotriffer et al., were utilized to compare the predictive capability of MFA and conventional QSAR models. Among these five compounds, only l-chicoric acid belongs to cluster 1 and the other four belong to cluster 2. MFA models give better overall predictions and more importantly the activity of these test compounds is better predicted by the MFA model derived from the cluster each test compound belongs to. The necessity of dividing the inhibitors into two groups to obtain predictive QSAR models supports the likelihood of two separate binding sites.

L-Chicoric acid inhibits human immunodeficiency virus type 1 integration in vivo and is a noncompetitive but reversible inhibitor of HIV-1 integrase in vitro

The human immunodeficiency virus (HIV) integrase (IN) must covalently join the viral cDNA into a host chromosome for productive HIV infection. l-Chicoric acid ( l-CA) enters cells poorly but is a potent inhibitor of IN in vitro. Using quantitative real-time polymerase chain reaction (PCR), l-CA inhibits integration at concentrations from 500 nM to 10 μM but also inhibits entry at concentrations above 1 μM. Using recombinant HIV IN, steady-state kinetic analyses with l-CA were consistent with a noncompetitive or irreversible mechanism of inhibition. IN, in the presence or absence of l-CA, was successively washed. Inhibition of IN diminished, demonstrating that l-CA was reversibly bound to the protein. These data demonstrate that l-CA is a noncompetitive but reversible inhibitor of IN in vitro and of HIV integration in vivo. Thus, l-CA likely interacts with amino acids other than those which bind substrate.

Catechol‐Substituted L‐Chicoric Acid Analogues as HIV Integrase Inhibitors.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Catechol-Substituted l-Chicoric acid analogues as HIV integrase inhibitors

HIV integrase catalyzes the integration of HIV DNA copy into the host cell DNA, which is essential for the production of progeny viruses. l-Chicoric acid and dicaffeoylquinic acids, isolated from plants, are well known potent inhibitors of HIV integrase. The common structural features of these inhibitors are caffeic acid derivatives connected to tartaric acid or quinic acid through ester bonds. In the present study, we have synthesized and tested the inhibitory activities of a new type of HIV IN inhibitors, which has catechol groups in place of caffeoyl groups in the structure of l-chicoric acid. Upon substitution of catechol groups at succinic acid, pyrrole-dicarboxylic acid, maleimide or maleic anhydride, the inhibitory activities (IC50=3.8–23.6μM) were retained or remarkably increased when compared to parent compound l-chicoric acid (IC50=13.7μM).

Caffeoyl naphthalenesulfonamide derivatives as HIV integrase inhibitors

HIV-1 integrase (IN) is an essential enzyme for retroviral replication and a rational target for the design of anti-AIDS drugs. In the present study, we have designed, synthesized and tested a series of caffeoyl naphthalenesulfonamide derivatives as HIV integrase inhibitors. Among these compounds, we found that HIV integrase inhibitory activities of compounds III-3 and III-4 were more potent than l-chicoric acid (IC 50=11.8 μg/mL) and others were comparable to l-chicoric acid. Furthermore, the structure–activity relationships of these compounds were studied. The information gathered from this paper will be useful in the development and design of HIV-1 integrase inhibitors in the future.