Synthesis of 3-aryl-4-(N-aryl)aminocoumarins via photoredox arylation and the evaluation of their biological activity.

A new series of 3-aryl-4-(N-aryl)aminocoumarins was synthesized in two steps starting from the natural product 4-hydroxycoumarin using the photoredox catalysis for the key step. These conditions reactions allowed to make CC bonds is up to 95% yields in mild conditions, easy operation, in an environmentally benign way, and are compatible with several patterns of substitution. The biological activity of the new compounds was tested in vitro against MCF-7, MDA-MB-231, and CCD-1072Sk cancer cell lines, as soon as to promastigotes and intracellular amastigotes of Leishmania amazonensis. Compounds 17d, 17s and 17x showed activity against promastigote forms (IC50 = 5.96 ± 3.210, 9.05 ± 2.855 and 5.65 ± 2.078 µM respectively), and compound 17x presented the best activity against L. amazonensis amastigote intracellular form (IC50 = 9.6 ± 1.148 µM), no BALB/c peritoneal macrophage cytotoxicity at assayed concentrations (CC50 > 600 µM), and high selectivity to parasites over the mammalian cells (Selectivity Index > 62.2). There was no expressive activity for the cancer cell lines. Single crystal X-ray diffraction analysis was employed for structural elucidation of compounds 17a and 17s. In silico analyses of physicochemical, pharmacokinetic, and toxicological properties suggest that compound 17x is a potential candidate for anti-leishmaniasis drugs.

Design and synthesis of aminocoumarin derivatives as DPP-IV inhibitors and anticancer agents.

DPP-IV "a moonlighting protein" has immerged as promising pathway to control Type 2 diabetes as well as found to play key role in earlier stages of cancer. Here we have reported design, synthesis and applications of aminocoumarin derivatives as DPP-IV inhibitors. Compounds have been synthesized and studied for their DPP-IV inhibition activity. Three compounds have shown moderate inhibition at 100 µM concentration. All compounds were also screened for their anticancer activity against A549 (Lung cancer cell line), MCF-7 (Breast cancer cell line) using MTT assay. One of the compounds has shown very good anticancer activity with IC50 value 24 ±â€¯0.1 nM against A549 cell line.

New 3-(heteroaryl)-2-iminocoumarin-based borate complexes: synthesis, photophysical properties, and rational functionalization for biosensing/biolabeling applications.

Members of a series of boron difluoride complexes with 3-(heteroaryl)-2-iminocoumarin ligands bearing both a phenolic hydroxyl group (acting as a fluorogenic center) and an N-aryl substituent (acting as a stabilizing moiety) have been synthesized in good yields by applying a straightforward two-step method. These novel fluorogenic dyes belong to the family of "Boricos" (D. Frath et al., Chem. Commun.- 2013, 49, 4908-4910) and are the first examples of phenol-based fluorophores of which the photophysical properties in the green-yellow spectral range are dramatically improved by N,N-chelation of a boron atom. Modulation of their fluorescence properties through reversible chemical modification of their phenol moieties has been demonstrated by the preparation of the corresponding 2,4-dinitrophenyl (DNP) ethers, which led to a dramatic "OFF-ON" fluorescence response upon reaction with thiols. Additionally, to expand the scope of these "7-hydroxy-Borico" derivatives, particularly in biolabeling, amine or carboxylic acid functionalities amenable to (bio)conjugation have been introduced within their scaffold. Their utility has been demonstrated in the preparation of fluorescent bovine serum albumin (BSA) conjugates and "Borico"-DOTA-like scaffolds in an effort to design novel monomolecular multimodal fluorescence- radioisotope imaging agents.

Antimicrobial and antioxidant activities of new metal complexes derived from 3-aminocoumarin.

3-Aminocoumarin (L) has been synthesized and used as a ligand for the formation of Cr(III), Ni(II), and Cu(II) complexes. The chemical structures were characterized using different spectroscopic methods. The elemental analyses revealed that the complexes where M=Ni(II) and Cu(II) have the general formulae [ML(2)Cl(2)], while the Cr(III) complex has the formula [CrL(2)Cl(2)]Cl. The molar conductance data reveal that all the metal chelates, except the Cr(III) one, are non-electrolytes. From the magnetic and UV-Visible spectra, it is found that these complexes have octahedral structures. The stability for the prepared complexes was studied theoretically using Density Function Theory. The total energy for the complexes was calculated and it was shown that the copper complex is the most stable one. Complexes were tested against selected types of microbial organisms and showed significant activities. The free radical scavenging activity of metal complexes have been determined by measuring their interaction with the stable free radical DPPH and all the compounds have shown encouraging antioxidant activities.

4-Aminocoumarin based Aroylthioureas as Potential Jack Bean Urease Inhibitors; Synthesis, Enzyme Inhibitory Kinetics and Docking Studies.

BACKGROUND: Urease enzyme catalyzes the hydrolysis of urea into ammonia and CO2, excess ammonia causes global warming and crop reduction. Ureases are also responsible for certain human diseases such as stomach cancer, peptic ulceration, pyelonephritis, and kidney stones. New urease inhibitors are developed to get rid of such problems. OBJECTIVE: This article describes the synthesis of a series of novel 1-aroyl-3-(2-oxo-2H-chromen-4- yl)thiourea derivatives (5a-j) as Jack bean urease inhibitors. METHODS: Freshly prepared aryl isothiocyanates were reacted with 4-aminocoumarin in the same pot in an anhydrous medium of acetone. The structures of the title thioureas (5a-j) were ascertained by their spectroscopic data. The inhibitory effects against jack bean urease were determined. RESULTS: It was found that compounds 5i and 5j showed excellent activity with IC50 values 0.0065 and 0.0293, µM respectively. Compound 5i bearing 4-methyl substituted phenyl ring plays a vital role in enzyme inhibitory activity. The kinetic mechanism analyzed by Lineweavere-Burk plots revealed that compound 5i inhibits the enzyme non-competitively. The Michaelis-Menten constant Km and inhibition constants Ki calculated from Lineweavere-Burk plots for compound 5i are 4.155mM and 0.00032µM, respectively. The antioxidant activity results displayed that compound 5j showed excellent radical scavenging activity. The cytotoxic effects determined against brine shrimp assay showed that all of the synthesized compounds are non-toxic to shrimp larvae. Molecular docking studies were performed against target protein (PDBID 4H9M) and it was determined that most of the synthesized compounds exhibited good binding affinity with the target protein. Molecular dynamics simulation (MDS) results revealed that compound 5i forms a stable complex with target protein showing little fluctuation. CONCLUSIONS: Based upon our investigations, it is proposed that 5i derivative may serve as a lead structure for devising more potent urease inhibitors.

A Convenient Method for the Synthesis of Chromeno[4,3-b]pyridines Via Three-component Reaction.

AIM AND OBJECTIVE: The importance of Chromeno[4,3-b]pyridines in bioactive compounds, highlighted the ongoing research on developing novel methods for the construction of this heterocyclic scaffold. Regarding the advantageous features of multi-component reactions in organic synthesis, we will try to synthesize pyridocoumarins through this method. MATERIALS AND METHODS: Chromeno[4,3-b]pyridines were conveniently prepared from a threecomponent condensation reaction between 4-hydroxy coumarin, ammonia and ethyl 2,4-dioxo-4- arylbutanoates in refluxing n-propanol. The synthesized compounds were characterized by NMR, IR and Mass spectroscopy. RESULTS: The reaction proceeded through an in situ formed 4-amino coumarin, affording eight new target compounds in good yields. CONCLUSION: This method introduce a novel approach to ethyl 4-aryl-5-oxo-5H-chromeno[4,3- b]pyridine-2-carboxylate derivatives and allow organic chemists to prepare 4-aminocoumarin in reaction medium.

A novel three-fluorophore system as a ratiometric sensor for multiple protease detection.

A synthetic three-fluorophore system with two enzymatically cleavable linkers has been developed for the simultaneous detection of two proteases in a mixture. The probe was designed to afford single excitation/triple emission ratiometric detection through a fluorescence change during the cleavage of a peptide linker. The developed assays were verified for trypsin and chymotrypsin as the model enzymes.

Synthesis and evaluation of coumermycin A1 analogues that inhibit the Hsp90 protein folding machinery.

[structure: see text] The coumarin antibiotics are not only potent inhibitors of DNA gyrase but also represent the most effective C-terminal inhibitors of 90 kDa heat shock proteins (Hsp90) reported thus far. In contrast to the N-terminal ATP-binding site, little is known about the Hsp90 C-terminus. In addition, very limited structure-activity relationships exist between this class of natural products and Hsp90. In this letter, the syntheses of dimeric coumarin analogues are presented along with their inhibitory values in breast cancer cell lines.

Triggering HIV polyprotein processing by light using rapid photodegradation of a tight-binding protease inhibitor.

HIV protease (PR) is required for proteolytic maturation in the late phase of HIV replication and represents a prime therapeutic target. The regulation and kinetics of viral polyprotein processing and maturation are currently not understood in detail. Here we design, synthesize, validate and apply a potent, photodegradable HIV PR inhibitor to achieve synchronized induction of proteolysis. The compound exhibits subnanomolar inhibition in vitro. Its photolabile moiety is released on light irradiation, reducing the inhibitory potential by 4 orders of magnitude. We determine the structure of the PR-inhibitor complex, analyze its photolytic products, and show that the enzymatic activity of inhibited PR can be fully restored on inhibitor photolysis. We also demonstrate that proteolysis of immature HIV particles produced in the presence of the inhibitor can be rapidly triggered by light enabling thus to analyze the timing, regulation and spatial requirements of viral processing in real time.

Targeting the heat shock protein 90 dimer with dimeric inhibitors.

The design, synthesis, and biological evaluation of conformationally constrained coumermycin A1 analogues are reported. Compounds were evaluated against both breast cancer (SKBr3 and MCF7) and prostate cancer (PC3 mm2, A549, and HT29) cell lines. Non-noviosylated coumermycin A1 analogues that manifest potent antiproliferative activity resulting from Hsp90 inhibition are provided, wherein replacement of the stereochemically complex noviose sugar with readily available piperidine rings resulted in ∼100 fold increase in antiproliferative activities as compared to coumermycin A1, producing small molecule Hsp90 inhibitors that exhibit nanomolar activities.

Aminocoumarins mutasynthesis, chemoenzymatic synthesis, and metabolic engineering.

The aminocoumarin antibiotics novobiocin, clorobiocin and coumermycin A(1) are formed by different Streptomyces strains and are potent inhibitors of bacterial gyrase. Their biosynthetic gene clusters have been analyzed in detail by genetic and biochemical investigations. Heterologous expression of these gene clusters by site-specific integration into the genome of the fully sequenced host Streptomyces coelicolor A3(2) readily results in an accumulation of the antibiotics in yields similar to the wildtype strains. In recent years, the aminocoumarins have developed into a model system for the generation of new antibiotics by genetic methods. Prior to heterologous expression in S. coelicolor, cosmids containing the complete biosynthetic clusters can be manipulated in Escherichia coli by lambda RED-mediated recombination, creating single or multiple gene replacements or gene deletions. Thereby, mutant strains are generated which are blocked in the synthesis of certain intermediates or in specific tailoring reactions. For instance, mutasynthetic experiments can subsequently be carried out to generate aminocoumarin antibiotics that contain modified acyl moieties attached to the aminocoumarin core, and chemoenzymatic synthesis can be employed for the acylation of the deoxysugar moiety of structural analogues of the aminocoumarin antibiotics. Metabolic engineering-the combination of gene deletions and foreign gene expression via replicative expression vectors-can be used to generate further structural variants of these antibiotics. These methods can be combined, allowing the generation of a wide variety of new compounds. This chapter may provide general pointers for the use of genetic methods in the generation of new antibiotics.

Design and total synthesis of a fluorescent phorboxazole A analog for cellular studies.

To enable studies to elucidate the intracellular processing and targeting of the potent cytostatic/apoptotic anticancer natural products phorboxazoles A and B, a fluorescent derivative has been developed. This involved the total syntheses of the terminal alkyne 33-O-Me-45,46-dehydrobromophorboxazole A (MDHBPA) and a terminal vinyl iodide derivative of the blue fluorescent dye N,N,-dimethyl-7-aminocoumarin (DMC). Sonogashira coupling of these partners provided enyne DMC-MDHBPA in high yield.