Advances in chromone-based copper(ii) Schiff base complexes: synthesis, characterization, and versatile applications in pharmacology and biomimetic catalysis.

Chromones are well known as fundamental structural elements found in numerous natural compounds and medicinal substances. The Schiff bases of chromones have a much wider range of pharmacological applications such as antitumor, antioxidant, anti-HIV, antifungal, anti-inflammatory, and antimicrobial properties. A lot of research has been carried out on chromone-based copper(ii) Schiff-base complexes owing to their role in the organometallic domain and promise as potential bioactive cores. This review article is centered on copper(ii) Schiff-base complexes derived from chromones, highlighting their diverse range of pharmacological applications documented in the past decade, as well as the future research opportunities they offer.

Natural product inspired diastereoselective synthesis of sugar-derived pyrano[3,2-c]quinolones and their in-silico studies.

Herein, we report the development of a diastereoselective and efficient route to construct sugar-derived pyrano[3,2-c]quinolones utilizing 1-C-formyl glycal and 4-hydroxy quinolone annulation. This methodology will open a route to synthesize nature inspired pyrano[3,2-c]quinolones. This is the first report for the stereoselective synthesis of sugar-derived pyrano[3,2-c]quinolones, where 100% stereoselectivity was observed. A total of sixteen compounds have been synthesized in excellent yields with 100% stereoselectivity. The molecular docking of the synthesized novel natural product analogues demonstrated their binding modes within the active site of type II topoisomerase. The results of the in-silico studies displayed more negative binding energies for the all the synthesized compounds in comparison to the natural product huajiosimuline A, indicating their affinity for the active pocket. Ten out of the sixteen novel synthesized compounds were found to have comparative or relatively more negative binding energy in comparison to the standard anti-cancer drug, doxorubicin. Additionally, the scalability and viability of this protocol was illustrated by the gram scale synthesis.

Recent advances in the synthesis and utility of thiazoline and its derivatives.

Thiazolines and their derivatives hold significant importance in the field of medicinal chemistry due to their promising potential as pharmaceutical agents. These molecular entities serve as critical scaffolds within numerous natural products, including curacin A, thiangazole, and mirabazole, and play a vital role in a wide array of physiological reactions. Their pharmacological versatility encompasses anti-HIV, neurological, anti-cancer, and antibiotic activities. Over the course of recent decades, researchers have extensively explored and developed analogs of these compounds, uncovering compelling therapeutic properties such as antioxidant, anti-tumor, anti-microbial, and anti-inflammatory effects. Consequently, thiazoline-based compounds have emerged as noteworthy targets for synthetic endeavors. In this review, we provide a comprehensive summary of recent advancements in the synthesis of thiazolines and thiazoline-based derivatives, along with an exploration of their diverse potential applications across various scientific domains.

Solvent-free synthesis and in-silico molecular docking study of (E)-3-(ß-C-glycosylmethylidene)-N-aryl/alkyl succinimides.

Globally, human papillomavirus (HPV) infection is the leading cause of mortality associated with cervical cancer, oral cancer (oropharyngeal), and head and neck squamous cell carcinoma (HNSCC). It is essential to explore anti-cancer drugs against life-threatening HPV infections. Aiming to search for potentially better anticancer agents, a small library of ß-C-glycosylated methylidene succinimides have been synthesized under bulk and mechanical grinding conditions using the Wittig olefination reaction. Thus, the reaction of different 2,3,4,6-tetra-O-benzyl-C-glycosyl aldehydes with N-aryl/alkyl maleimides in the presence of PPh3 at 25 °C under bulk and mechanical grinding conditions results in the formation of stereochemically defined (E)-3-(2,3,4,6-tetra-O-benzyl-C-glycosylmethylidene)-N-alkyl/phenyl succinimides, which upon debenzylation with 1 M BCl3 in DCM at -78 °C lead to the synthesis of (E)-3-(C-glycosylmethylidene)-N-alkyl/phenyl succinimides in good to excellent yields. The developed methodology is efficient and environmentally benign because there is no use of organic solvents, and the products are obtained in a stereochemically defined form and in high yields. The aqueous solubility of all synthesized ß-C-glycosylated methylidene succinimides makes them potential candidates for the evaluation of their different biological activities. In the present work, the synthesized glycosylated alkylidine succinimides were subjected to an in-silico molecular docking study against the E6 oncoprotein of high-risk type HPV16, which is responsible for the inactivation of the tumor suppressor p53 protein. Analysis of the molecular docking data revealed that the synthesized compounds are effective inhibitors of HPV infection, which is the cause of oral, head and neck, and cervical cancer. In comparison with the positive control 5-FU, an anti-cancer drug used in chemotherapy, more than fifteen compounds were found to be better E6 protein inhibitors.

Efficient and stereoselective synthesis of sugar fused pyrano[3,2-c]pyranones as anticancer agents.

A highly stereoselective, efficient and facile route was achieved for the synthesis of novel and biochemically potent sugar fused pyrano[3,2-c]pyranone derivatives starting from inexpensive, naturally occurring d-galactose and d-glucose. First, ß-C-glycopyranosyl aldehydes were synthesized from these d-hexose sugars in six steps, with overall yields 41-55%. Next, two different 1-C-formyl glycals were synthesized from these ß-C-glycopyranosyl aldehydes by treatment in basic conditions. The optimization of reaction conditions was carried out following reactions between 1-C-formyl galactal and 4-hydroxycoumarin. Next, 1-C-formyl galactal and 1-C-formyl glucal were treated with nine substituted 4-hydroxy coumarins at room temperature (25 °C) in ethyl acetate for ∼1-2 h in the presence of l-proline to obtain exclusively single diastereomers of pyrano[3,2-c]pyranone derivatives in excellent yields. Four compounds were found to be active for the MCF-7 cancer cell line. The MTT assay, apoptosis assay and migration analysis showed significant death of the cancer cells induced by the synthesized compounds.

Recent advances in synthesis of sugar and nucleoside coumarin conjugates and their biological impact.

Naturally occurring coumarin and sugar molecules have a diverse range of applications along with superior biocompatibility. Coumarin, a member of the benzopyrone family, exhibits a wide spectrum of medicinal properties, such as anti-coagulant, anti-bacterial, anti-tumor, anti-oxidant, anti-cancer, anti-inflammatory and anti-viral activities. The sugar moiety functions as the central scaffold for the synthesis of complex molecules, attributing to their excellent biocompatibility, well-defined stereochemistry, benign nature and outstanding aqueous solubility. When the coumarin moiety is conjugated with the sugar or nucleoside molecule, the resulting conjugates exhibit significant biological properties. Due to the remarkable growth of such bioconjugates in the field of science over the last decade, owing to their future prospect as a potential bioactive core, an update to this area is very much needed. The present review focusses on the synthesis, characterization and the various therapeutic applications of coumarin conjugates, i.e., sugar and nucleoside coumarin conjugates along with their perspective for future research.

Natural Compounds and Their Analogues as Potent Antidotes against the Most Poisonous Bacterial Toxin.

Botulinum neurotoxins (BoNTs), the most poisonous proteins known to humankind, are a family of seven (serotype A to G) immunologically distinct proteins synthesized primarily by different strains of the anaerobic bacterium Clostridium botulinum Being the causative agents of botulism, the toxins block neurotransmitter release by specifically cleaving one of the three soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins, thereby inducing flaccid paralysis. The development of countermeasures and therapeutics against BoNTs is a high-priority research area for public health because of their extreme toxicity and potential for use as biowarfare agents. Extensive research has focused on designing antagonists that block the catalytic activity of BoNTs. In this study, we screened 300 small natural compounds and their analogues extracted from Indian plants for their activity against BoNT serotype A (BoNT/A) as well as its light chain (LCA) using biochemical and cellular assays. One natural compound, a nitrophenyl psoralen (NPP), was identified to be a specific inhibitor of LCA with an in vitro 50% inhibitory concentration (IC50) value of 4.74 ± 0.03 µM. NPP was able to rescue endogenous synaptosome-associated protein 25 (SNAP-25) from cleavage by BoNT/A in human neuroblastoma cells with an IC50 of 12.2 ± 1.7 µM, as well as to prolong the time to the blocking of neutrally elicited twitch tensions in isolated mouse phrenic nerve-hemidiaphragm preparations.IMPORTANCE The long-lasting endopeptidase activity of BoNT is a critical biological activity inside the nerve cell, as it prompts proteolysis of the SNARE proteins, involved in the exocytosis of the neurotransmitter acetylcholine. Thus, the BoNT endopeptidase activity is an appropriate clinical target for designing new small-molecule antidotes against BoNT with the potential to reverse the paralysis syndrome of botulism. In principle, small-molecule inhibitors (SMIs) can gain entry into BoNT-intoxicated cells if they have a suitable octanol-water partition coefficient (log P) value and other favorable characteristics (P. Leeson, Nature 481:455-456, 2012, https://doi.org/10.1038/481455a). Several efforts have been made in the past to develop SMIs, but inhibitors effective under in vitro conditions have not in general been effective in vivo or in cellular models (L. M. Eubanks, M. S. Hixon, W. Jin, S. Hong, et al., Proc Natl Acad Sci U S A 104:2602-2607, 2007, https://doi.org/10.1073/pnas.0611213104). The difference between the in vitro and cellular efficacy presumably results from difficulties experienced by the compounds in crossing the cell membrane, in conjunction with poor bioavailability and high cytotoxicity. The screened nitrophenyl psoralen (NPP) effectively antagonized BoNT/A in both in vitro and ex vivo assays. Importantly, NPP inhibited the BoNT/A light chain but not other general zinc endopeptidases, such as thermolysin, suggesting high selectivity for its target. Small-molecule (nonpeptidic) inhibitors have better oral bioavailability, better stability, and better tissue and cell permeation than antitoxins or peptide inhibitors.

Antiplasmodial activity of hydroxyethylamine analogs: Synthesis, biological activity and structure activity relationship of plasmepsin inhibitors.

Malaria, particularly in endemic countries remains a threat to the human health and is the leading the cause of mortality in the tropical and sub-tropical areas. Herein, we explored new C2 symmetric hydroxyethylamine analogs as the potential inhibitors of Plasmodium falciparum (P. falciparum; 3D7) in in-vitro cultures. All the listed compounds were also evaluated against crucial drug targets, plasmepsin II (Plm II) and IV (Plm IV), enzymes found in the digestive vacuole of the P. falciparum. Analog 10f showed inhibitory activities against both the enzymes Plm II and Plm IV (Ki, 1.93 ±â€¯0.29 µM for Plm II; Ki, 1.99 ±â€¯0.05 µM for Plm IV). Among all these analogs, compounds 10g selectively inhibited the activity of Plm IV (Ki, 0.84 ±â€¯0.08 µM). In the in vitro screening assay, the growth inhibition of P. falciparum by both the analogs (IC50, 2.27 ±â€¯0.95 µM for 10f; IC50, 3.11 ±â€¯0.65 µM for 10g) displayed marked killing effect. A significant growth inhibition of the P. falciparum was displayed by analog 12c with IC50 value of 1.35 ±â€¯0.85 µM, however, it did not show inhibitory activity against either Plms. The hemolytic assay suggested that the active compounds selectively inhibit the growth of the parasite. Further, potent analogs (10f and 12c) were evaluated for their cytotoxicity towards mammalian HepG2 and vero cells. The selectivity index (SI) values were noticed greater than 10 for both the analogs that suggested their poor toxicity. The present study indicates these analogs as putative lead structures and could serve as crucial for the development of new drug molecules.

Protective effects of new antioxidant compositions of 4-methylcoumarins and related compounds with dl-α-tocopherol and l-ascorbic acid.

BACKGROUND: Coumarin derivatives possess a wide range of biological activities. By functionalization of the parent coumarin skeleton that has neither antioxidant nor biological activity, a series of new bio-antioxidants has been designed. RESULTS: New antioxidant compositions (equimolar binary and ternary mixtures) of eight 4-methylcoumarins and three related compounds have been tested and different effects between individual components have been observed: synergism (positive effect), additivism (summary effect) and antagonism (negative effect). Higher oxidative stability of the lipid substrate was obtained in the presence of the new antioxidant compositions of the studied compounds with dl-α-tocopherol and l-ascorbic acid. The role of each component in the antioxidant compositions of ternary mixtures has been identified by using new equations composed by the authors. CONCLUSION: All ternary mixtures demonstrate synergism as a result of continuous regeneration of dl-α-tocopherol from the studied antioxidants and l-ascorbic acid. Theoretical calculations have been probed as indicators of the expected effects between the individual components in a binary mixture. © 2018 Society of Chemical Industry.

Synthesis of macromolecular systems via lipase catalyzed biocatalytic reactions: applications and future perspectives.

Enzymes, being remarkable catalysts, are capable of accepting a wide range of complex molecules as substrates and catalyze a variety of reactions with a high degree of chemo-, stereo- and regioselectivity in most of the reactions. Biocatalysis can be used in both simple and complex chemical transformations without the need for tedious protection and deprotection chemistry that is very common in traditional organic synthesis. This current review highlights the applicability of one class of biocatalysts viz."lipases" in synthetic transformations, the resolution of pharmaceutically important small molecules including polyphenols, amides, nucleosides and their precursors, the development of macromolecular systems (and their applications as drug/gene carriers), flame retardants, polymeric antioxidants and nanocrystalline solar cells, etc.

Hydroxyethylamine Based Phthalimides as New Class of Plasmepsin Hits: Design, Synthesis and Antimalarial Evaluation.

A novel class of phthalimides functionalized with privileged scaffolds was designed, synthesized and evaluated as potential inhibitors of plasmepsin 2 (Ki: 0.99 ± 0.1 µM for 6u) and plasmepsin 4 (Ki: 3.3 ± 0.3 µM for 6t), enzymes found in the digestive vacuole of the plasmodium parasite and considered as crucial drug targets. Three compounds were identified as potential candidates for further development. The listed compounds were also assayed for their antimalarial efficacy against chloroquine (CQ) sensitive strain (3D7) of Plasmodium falciparum. Assay of twenty seven hydroxyethylamine derivatives revealed four (5e, 6j, 6o and 6s) as strongly active, which were further evaluated against CQ resistant strain (7GB) of P. falciparum. Compound 5e possessing the piperidinopiperidine moiety exhibited promising antimalarial activity with an IC50 of 1.16 ± 0.04 µM. Further, compounds 5e, 6j, 6o and 6s exhibited low cytotoxic effect on MCF-7 cell line. Compound 6s possessing C2 symmetry was identified as the least cytotoxic with significant antimalarial activity (IC50: 1.30 ± 0.03 µM). The combined presence of hydroxyethylamine and cyclic amines (piperazines and piperidines) was observed as crucial for the activity. The current studies suggest that hydroxyethylamine based molecules act as potent antimalarial agent and may be helpful in drug development.

Antigiardial activity of novel triazolyl-quinolone-based chalcone derivatives: when oxygen makes the difference.

Giardiasis is a common diarrheal disease worldwide caused by the protozoan parasite Giardia intestinalis. It is urgent to develop novel drugs to treat giardiasis, due to increasing clinical resistance to the gold standard drug metronidazole (MTZ). New potential antiparasitic compounds are usually tested for their killing efficacy against G. intestinalis under anaerobic conditions, in which MTZ is maximally effective. On the other hand, though commonly regarded as an 'anaerobic pathogen,' G. intestinalis is exposed to relatively high O2 levels in vivo, living attached to the mucosa of the proximal small intestine. It is thus important to test the effect of O2 when searching for novel potential antigiardial agents, as outlined in a previous study [Bahadur et al. (2014) Antimicrob. Agents Chemother. 58, 543]. Here, 45 novel chalcone derivatives with triazolyl-quinolone scaffold were synthesized, purified, and characterized by high resolution mass spectrometry, (1)H and (13)C nuclear magnetic resonance and infrared spectroscopy. Efficacy of the compounds against G. intestinalis trophozoites was tested under both anaerobic and microaerobic conditions, and selectivity was assessed in a counter-screen on human epithelial colorectal adenocarcinoma cells. MTZ was used as a positive control in the assays. All the tested compounds proved to be more effective against the parasite in the presence of O2, with the exception of MTZ that was less effective. Under anaerobiosis eighteen compounds were found to be as effective as MTZ or more (up to three to fourfold); the same compounds proved to be up to >100-fold more effective than MTZ under microaerobic conditions. Four of them represent potential candidates for the design of novel antigiardial drugs, being highly selective against Giardia trophozoites. This study further underlines the importance of taking O2 into account when testing novel potential antigiardial compounds.

Design, synthesis and biological evaluation of functionalized phthalimides: a new class of antimalarials and inhibitors of falcipain-2, a major hemoglobinase of malaria parasite.

Phthalimides functionalized with cyclic amines were synthesized, characterized and screened for their in vitro antimalarial efficacy against Plasmodium falciparum (Pf3D7). Of all the listed phthalimides evaluated, 14 and 24 were identified as potent antimalarial agents as advocated by assessment of their ability to inhibit [(3)H] hypoxanthine incorporation in the nucleic acid of parasites. In addition, phthalimides 14 and 24 were incubated for 60 and 90h and an enhanced antimalarial effect was noticed with increase in time to great extent. A reduction in IC50 values was observed with increase in exposure time of the parasite to the compounds. A symmetric phthalimide, 24 possessing piperazine as linker unit was identified as the most potent antimalarial agent with IC50 values of 5.97±0.78, 2.0±1.09 and 1.1±0.75µM on incubation period of 42, 60 and 90h, respectively. The abnormal morphologies such as delay in developmental stages, growth arrest and condensed nuclei of parasite were observed with the aid of microscopic studies upon exposure with 14 and 24. The evaluation of 14 and 24 against chloroquine resistant strain, (Pf7GB) of P. falciparum afforded IC50 values, 13.29±1.20 and 7.21±0.98µM, respectively. The combination of 24 with artemisinin (ART) showed enhanced killing of parasite against Pf3D7. Further, all phthalimides were evaluated for their activity against falcipain-2 (FP2), a major hemoglobinase of malarial parasite. The enzymatic assay afforded 6 as most active member against FP2. To the best of our knowledge this is the initial study represents phthalimide protected amino acids functionalized with cyclic amines as potent antimalarial agents.

Functionalized hydroxyethylamine based peptide nanostructures as potential inhibitors of falcipain-3, an essential proteases of Plasmodium falciparum.

Self-assembled peptide based nanostructures gained enough popularity due to their easy biocompatibility and numerous potential applications. An excellent model of self-assembly of hydroxyethylamine based peptide nanostructures was synthesized and characterized by DLS and TEM. Spherical nano structures of I and III were observed with particle size ∼50 and ∼80nm, respectively. Further, I and III were screened against anti-malarial target, falcipain-3 (FP3), a crucial cysteine protease involved as a major hemoglobinase of Plasmodium falciparum. Interestingly, compound III completely inhibited the activity of FP3. The effective concentration (1.5µM) of III found to be more potent than I. This biochemical result was substantiated by molecular-docking studies indicating III to be best inhibitor of FP3. This is the first report showing that bis hydroxethylamine based peptide nanostructures could be very effective inhibitor of malarial cysteine proteases.

Ethyl 3',4',5'-trimethoxythionocinnamate modulates NF-κB and Nrf2 transcription factors.

Recently, we identified a novel cinnamate analog, ethyl 3',4',5'-trimethoxythionocinnamate (ETMTC) as a potent inhibitor of cell adhesion molecules (CAMs), such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. However, its mechanism of action has not been elucidated so far. Since, nuclear factor-kappa B (NF-κB) is the major transcription factor involved in the regulation of ICAM-1, VCAM-1 and E-selectin expression, we determined the status of NF-κB activation in ETMTC treated human endothelial cells. Here, we demonstrate that ETMTC inhibits TNF-α-induced nuclear translocation and activation of NF-κB by inhibiting phosphorylation and degradation of IκBα. The inhibition of IκBα phosphorylation and degradation by ETMTC was found to be due to its ability to inhibit IκB kinase activity. In addition, oxidative stress is known to regulate NF-κB activation through TNF-α signaling cascade, therefore, we examined the effect of ETMTC on TNF-α-induced reactive oxygen species generation. We observed that ETMTC significantly inhibits TNF-α-induced reactive oxygen species generation in endothelial cells. To further elucidate the anti-oxidant potential of ETMTC, we examined its effect on induction of anti-oxidant genes viz. glutamate-cysteine ligase, modifier subunit (GCLM), heme oxygenase-1 (HO1) and NAD (P)H:quinone oxidoreductase 1 (NQO1) in human bronchial epithelial cells. Interestingly, ETMTC significantly induces the anti-oxidant genes viz. GCLM, HO1 and NQO1 by activating nuclear factor-erythroid 2 p45-related factor 2 (Nrf2). Thus, ETMTC could be useful towards developing potent anti-inflammatory molecules.

A novel cinnamate derivative attenuates asthma features and reduces bronchial epithelial injury in mouse model.

Airway epithelial injury is the hallmark of various respiratory diseases and therapeutic targeting of epithelial injury could be an effective strategy for controlling these diseases. We recently reported that a novel cinnamate, ethyl 3',4',5'-trimethoxythionocinnamate (ETMTC) derived from Piper longum derivative, was most potent among various cinnamate derivatives in inhibiting inflammatory cell adhesion molecules (CAMs). In this study, we investigated the effects of ETMTC on the features of allergic asthma and epithelial injury in a murine model. ETMTC treatment to ovalbumin sensitized and challenged mice during ovalbumin challenge reduced airway hyperresponsiveness, and airway inflammation. This attenuation of asthma features was associated with the reduction in the expressions of various CAMs, NF-κB activation, Th2 cytokines, eotaxin and 8-isoprostane that were estimated in lung homogenates. Further, it increased activities of mitochondrial complexes I and IV in lung mitochondria and reduced cytochrome c and caspase 9 activities in lung cytosol. In addition, it reduced the levels of oxidative DNA damage marker in bronchoalveolar lavage fluid and DNA fragmentation of bronchial epithelia in lung sections. Further, ETMTC not only increased the levels of 15-(S)-hydroxyeicosatetraenoic acid, suppressor of airway remodeling, but also inhibited goblet cell metaplasia and sub-epithelial fibrosis. These results demonstrate that ETMTC reduces epithelial injury and mitochondrial dysfunction associated with allergic asthma and thus ETMTC could be useful to develop efficient therapeutic molecule against asthma.

Arylalkyl ketones, benzophenones, desoxybenzoins and chalcones inhibit TNF-α induced expression of ICAM-1: structure-activity analysis.

The interaction between leukocytes and the vascular endothelial cells (EC) via cellular adhesion molecules plays an important role in the pathogenesis of various inflammatory and autoimmune diseases. Small molecules that block these interactions have been targeted as potential therapeutic agents against acute and chronic inflammatory diseases. In an effort to identify potent intercellular cell adhesion molecule-1 (ICAM-1) inhibitors, a large number of arylalkyl ketones, benzophenones, desoxybenzoins and chalcones and their analogs (54 in total) have been synthesized and screened for their ICAM-1 inhibitory activity. The structure-activity relationship studies of these compounds identified three potent chalcone derivatives and also demonstrated the possible mechanism for their ICAM-1 inhibitory activities. The most active compound was found to be 79.

Novel natural product-based cinnamates and their thio and thiono analogs as potent inhibitors of cell adhesion molecules on human endothelial cells.

In the present study, we report the design and synthesis of novel analogs of cinnamates, thiocinnamates and thionocinnamates and evaluated the potencies of these analogs to inhibit TNF-α induced ICAM-1 expression on human endothelial cells. By using whole cell-ELISA, our screening data demonstrated that ethyl 3',4',5'-trimethoxythionocinnamate (ETMTC) is the most potent inhibitor of TNF-α induced ICAM-1, VCAM-1 and E-selectin. As functional consequences, ETMTC abrogated TNF-α induced adhesion of neutrophils to the endothelial monolayer. Structure-activity relationship studies revealed the critical role of the chain-length of the alkyl group in the alcohol moiety, number of methoxy groups in the aromatic ring of the cinnamoyl moiety and the presence of the α, ß- C-C double bond in the thiocinnamates and thionocinnamates.

In vitro interactions of coumarins with iron.

Coumarins are a large group of natural substances with diverse pharmacological properties that may predetermine some of them for the prevention and/or treatment of cardiovascular diseases and also other pathologies. Free iron participates in the production of reactive oxygen species (ROS) and plays an important role in the pathogenesis of cardiovascular diseases. Therefore, chelation of iron may attenuate some ROS consequences, but on the other hand, reduction of ferric ions to ferrous ones is unfavourable and leads to intensification of ROS production. In this study, we have examined the interaction of iron with coumarins which has been rarely analyzed. A series of naturally occurring and chemically synthesized 4-methylcoumarins were analyzed for their ferrous and total iron-chelating properties and compared with standard iron chelator deferoxamine. The iron chelation activity was assessed by a simple spectrophotometric approach based on the specific indicator for ferrous ions--ferrozine. The methodology was also extended for the measurement of total iron. Among the tested coumarins, ortho-dihydroxyderivatives were the most potent iron chelators and 7,8-dihydroxy-4-methylcoumarin even reached the efficiency of deferoxamine in neutral pH. However, these ortho-dihydroxycoumarins did not bind iron firmly in acidic conditions (e.g., in acute myocardial infarction) and, moreover, they reduced ferric ions that could lead to intensification of the Fenton chemistry. Other tested coumarins did not substantially chelate iron with the exception of ortho-diacetoxycoumarins. Conclusively, the use of iron-chelating coumarins in acidic conditions may be disadvantageous in contrast to neutral conditions.

A chromone analog inhibits TNF-alpha induced expression of cell adhesion molecules on human endothelial cells via blocking NF-kappaB activation.

The interaction between leukocytes and the vascular endothelial cells (EC) via cellular adhesion molecules plays an important role in various inflammatory and immune diseases. The molecules that block these interactions have been targeted as potential therapeutic targets for acute and chronic inflammatory diseases. In an effort to develop potent cell adhesion molecule inhibitors, a series of chromone derivatives bearing alkoxycarbonylvinyl unit at the C-3 position, that is, the chromones 8a-d and 9a-d, were designed and synthesized, and evaluated for their ICAM-1 inhibitory activity on human endothelial cells as well as their effect on NADPH-catalyzed rat microsomal lipid peroxidation. A structure-activity relationship was established and we found that length of the alkyl moiety of the chromone-3-yl-acrylate is important for this activity. Further, we found that incorporation of unsaturation in the alcohol moiety increases the potential of the compound for the inhibition of TNF-alpha induced expression of ICAM-1 and also for the inhibition of lipid peroxidation. Out of the screened compounds, the most potent compound ethyl trans-3-(4-oxo-4H-1-benzopyran-3-yl)-acrylate (8a) was taken for further study. We have found that compound 8a also significantly inhibited the TNF-alpha induced expression of VCAM-1 and E-selectin, which play key roles in various inflammatory diseases. This inhibition was found to be concentration dependent. The functional consequences of inhibiting cell adhesion molecules were studied by performing cell-adhesion assay. We found that compound 8a significantly blocks the adhesion of neutrophils to endothelial monolayer. To elucidate the molecular mechanism of inhibition of cell adhesion molecules, we investigated the status of nuclear transcription factor-kappaB (NF-kappaB) and were able to establish that compound 8a significantly blocked the TNF-alpha induced activation of NF-kappaB.