Mining for antifungal agents to inhibit biofilm formation of Candida albicans: A study on green synthesis, antibiofilm, cytotoxicity, and in silico ADME analysis of 2-amino-4H-pyran-3-carbonitrile derivatives.

Candida albicans (C. albicans) biofilm infections are quite difficult to manage due to their resistance against conventional antifungal drugs. To address this issue, there is a desperate need for new therapeutic drugs. In the present study, a green and efficient protocol has been developed for the synthesis of 2-amino-4H-pyran-3-carbonitrile scaffolds 4a-i, 6a-j, and 8a-g by Knoevenagel-Michael-cyclocondensation reaction between aldehydes, malononitrile, and diverse enolizable C-H activated acidic compounds using guanidinium carbonate as a catalyst either under grinding conditions or by stirring at room temperature. This protocol is operationally simple, rapid, inexpensive, has easy workup and column-free purification. A further investigation of the synthesized compounds was conducted to examine their antifungal potential and their ability to inhibit the growth and development of biofilm-forming yeasts like fungus C. albicans. According to our findings, 4b, 4d, 4e, 6e, 6f, 6g, 6i, 8c, 8d, and 8g were found to be active and potential inhibitors for biofilm infection causing C. albicans. The inhibition of biofilm by active compounds were observed using field emission scanning electron microscopy (FESEM). Biofilm inhibiting compounds were also tested for in vitro toxicity by using 3T3-L1 cell line, and 4b, 6e, 6f, 6g, 6i, 8c, and 8d were found to be biocompatible. Furthermore, the in silico ADME descriptors revealed drug-like properties with no violation of Lipinski's rule of five. Hence, the result suggested that synthesized derivatives could serve as a useful aid in the development of novel antifungal compounds for the treatment of fungal infections and virulence in C. albicans.

Synthesis and antiproliferative activity of a tetrahydrofuran analog of FR901464.

FR901464 is a natural product that exhibits antiproliferative activity at single-digit nanomolar concentrations in cancer cells. Its tetrahydropyran-spiroepoxide covalently binds the spliceosome. Through our medicinal chemistry campaign, we serendipitously discovered that a bromoetherification formed a tetrahydrofuran. The tetrahydrofuran analog was three orders of magnitude less potent than the corresponding tetrahydropyran analogs. This study shows the significance of the tetrahydropyran ring that presents the epoxide toward the spliceosome.

2-Pyran-4-Ylidene Malononitrile Based Conjugated Microporous Polymers as Metal-Free Heterogeneous Photocatalysts for Organic Synthesis.

Photoactive conjugated microporous polymers (CMPs) as heterogeneous photocatalysts provide a sustainable alternative to classical metal-based semiconductor photosensitizers. However, previously reported CMPs are typically synthesized through metal catalyzed coupling reactions, which bears product separation, but also increases the price of materials. Herein, a new type of sp2 carbon linked DCM-CMPs are successfully designed and synthesized by organic base catalyzed Knoevenagel reaction using 2,6-Dimethyl-4H-pyran-4-ylidene-malononitrile and aromatic polyaldehydes as monomers. The new polymers feature inherent porosity, excellent stability, and fully π-conjugated skeleton with broad visible-light absorption. They effectively induce the synthesis of benzimidazole compounds under light irradiation, and exhibit wide substrate adaptability with outstanding recyclability.

Synthesis, Antimicrobial Evaluation, DFT, and Molecular Docking Studies of Pyrano [4,3-b] Pyranone and Pyrano[2,3-b]Pyridinone Systems.

Dehydroacetic acid (DHA) was utilized as a fundamental precursor in the synthesis of novel pyrano [4,3-b] pyran and pyrano [2,3-b] pyridine systems. Whereas, a new series of fused polyheteronuclear systems was achieved through the reaction of DHA with active methylene compounds such as malononitrile and pyrazolone. Whereas, the treatment of DHA 1 with cyclic ketones involving cyclohexanone and cyclododecanone afforded annulated tricyclic system 6 and spiro hybrid molecule 7. Also, the reaction of DHA 1 with cyanoacetamide derivatives 8 and 11 yielded their corresponding novel pyrano [2,3-b] pyridine-6-carbonitrile frameworks 9 and 12, respectively. Also, in silico predictive theoretical molecular docking studies for bioactive synthesized scaffolds against both HER2 and 6BBP displayed an optimistic result for compounds 2 b, 5, 9, and 12 highlighting their expediency as up-and-coming candidates for future preclinical trials. Additionally, all compounds were assessed as antibacterial agents against various types of four candidates of bacteria in the presence of ampicillin as a reference. Notably, compounds 6, 7, and 12 showed promising antibacterial potential against Bacillus subtilis with activity indexes (69.6, 91.3, and 82.6 %), respectively.

Synthesis and anti-tumor activity evaluation of salinomycin C20-O-alkyl/benzyl oxime derivatives.

Seventeen C20-O-alkyl/benzyl oxime derivatives were synthesized by a concise and effective method. Most of these derivatives showed tens to several hundred nanomolar IC50 values against HT-29 colorectal, HGC-27 gastric and MDA-MB-231 breast cancer cells, whose antiproliferative activity is 15-240 fold better than that of salinomycin. The C20-oxime etherified derivatives can coordinate potassium ions, and further adjust the cytosolic Ca2+ concentrations in HT-29 cells. The significant improvement of the potency should be attributed to the better ion binding and transport ability of the modified derivatives. In addition, the C20-O-alkyl/benzyl oxime derivatives showed much better selectivity indexes (SI) than salinomycin, indicating that they present lower neurotoxic risk.

A Highly Convergent Total Synthesis of Norhalichondrin B.

A new synthetic strategy for the total synthesis of norhalichondrin B featuring a highly convergent approach and our recently disclosed reverse approach for the synthesis of cyclic ether structural motifs is disclosed. Resulting in the shortest route to norhalichondrin B disclosed thus far, the reported total synthesis was achieved through the synthesis of two almost equally complex fragments whose coupling and short elaboration sequence featured an essential epimerization of the C16 stereocenter occurring concurrently with a simple acid-induced deprotection, a tactic based on a prior study along the synthetic route. This unprecedented strategy within the halichondrin family of natural products could find practical application to the synthesis of other more or less complex natural or designed halichondrin analogues.

Enantioselective Total Synthesis of (+)-Peniciketals A and B: Two Architecturally Complex Spiroketals.

The enantioselective total syntheses of (+)-peniciketals A and B, two members of a family of architecturally complex spiroketals, have been achieved. Key synthetic transformations comprise Type I Anion Relay Chemistry (ARC) to construct the benzannulated [6,6]-spiroketal skeleton, a Negishi cross-coupling/olefin cross-metathesis reaction sequence to generate the trans-enone structure, and a late-stage large fragment union exploiting our recently developed photoisomerization/cyclization tactic.

Synthesis of Rare 6-Deoxy-d-/l-Heptopyranosyl Fluorides: Assembly of a Hexasaccharide Corresponding to Campylobacter jejuni Strain CG8486 Capsular Polysaccharide.

Campylobacter jejuni is the leading cause of human diarrheal diseases and has been designated as one of highly resistant pathogens by the World Health Organization. The C. jejuni capsular polysaccharides feature broad existence of uncommon 6dHepp residues and have proven to be potential antigens to develop innovative antibacterial glycoconjugation vaccines. To address the lack of synthetic methods for rare 6dHepp architectures of importance, we herein describe a novel and efficient approach for the preparation of uncommon d-/l-6dHepp fluorides that have power as glycosylating agents. The synthesis is achieved by a C1-to-C5 switch strategy relying on radical decarboxylative fluorination of uronic acids arising from readily available allyl d-C-glycosides. To further showcase the application of this protocol, a structurally unique hexasaccharide composed of →3)-ß-d-6didoHepp-(1→4)-ß-d-GlcpNAc-(1→ units, corresponding to the capsular polysaccharide of C. jejuni strain CG8486 has been assembled for the first time. The assembly is characterized by highly efficient construction of the synthetically challenging ß-(1,2-cis)-d-ido-heptopyranoside by inversion of the C2 configuration of ß-(1,2-trans)-d-gulo-heptopyranoside, which is conveniently obtained by anchimerically assisted stereoselective glycosylation of the orthogonally protected 6dgulHepp fluoride. Ready accessibility of 6dHepp fluorides and the resulting glycans could serve as a rational starting point for the further development of synthetic vaccines fighting Campylobacter infection.

Practical Gram-Scale Synthesis of Iboxamycin, a Potent Antibiotic Candidate.

A gram-scale synthesis of iboxamycin, an antibiotic candidate bearing a fused bicyclic amino acid residue, is presented. A pivotal transformation in the route involves an intramolecular hydrosilylation-oxidation sequence to set the ring-fusion stereocenters of the bicyclic scaffold. Other notable features of the synthesis include a high-yielding, highly diastereoselective alkylation of a pseudoephenamine amide, a convergent sp3-sp2 Negishi coupling, and a one-pot transacetalization-reduction reaction to form the target compound's oxepane ring. Implementation of this synthetic strategy has provided ample quantities of iboxamycin to allow for its in vivo profiling in murine models of infection.

Daylight LED promotes photochemical ring contraction of 2-amine-4H-pyran-3-carbonitriles with consequent loss of their antifungal activity.

The initial objective of our work was to synthesize a series of 2-amino-4H-pyran-3-carbonitriles to be tested for their antifungal activities against economically relevant phytopathogenic fungi. Fourteen compounds were prepared in up to 94% yield and shown percentages of Botrytis cinerea inhibition above 70%. Despite the promising biological results, we observed that stock solutions prepared for biological tests showed color changing when kept for a few days on the laboratory bench, under room conditions, illuminated by common LED daylight tubes (4500-6000 k). This prompted us to investigate the possible photo-induced degradation of our compounds. FT-IR ATR experiments evidenced variations in the expected bands for functional of -amino-4H-pyran-3-carbonitriles stored under LED daylight. Following, HPLC-UV analysis showed reductions in the intensity of chromatographic peaks of 2-amino-4H-pyran-3-carbonitriles, and but not for solutions kept in the dark. A solution of (E)-2-amino-8-(4-nitrobenzylidene)-4-(4-nitrophenyl)-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile underwent 84.4% of conversion after 72 h of exposure to continuous LED daylight in a BOD chamber, and the reaction product was isolated in 36% yield and characterized as (E)-7-cyano-5-(4-nitrobenzylidene)-8-(4-nitrophenyl)bicyclo[4.2.0]oct-1(6)-ene-7-carboxamide (7*). Despite freshly prepared solutions of 2-amino-4H-pyran-3-carbonitriles produced antifungal activities, these solutions lost biological activity when left on the bench for a week. Besides, compound 7* formed from photo-induced degradation of 7 also showed no antifungal activity. With this, we hope to bring two contributions: (1) production of cyclobutenes through photochemical reactions of 2-amino-4H-pyran-3-carbonitriles can be carried out through exposure to simple white LED daylight; (2) biological applications of such 2-amino-4H-pyran-3-carbonitriles may be impaired by their poor photostability.

Synthesis of pyranochalcone derivatives and their inhibitory effect on NF-κB activation.

In an effort to identify novel inhibitors of nuclear factor kappa B (NF-κB), twenty five pyranochalcone derivatives were synthesized and evaluated for their in vitro activities against TNF-α induced NF-κB inhibition in HEK293T cells. Among all of these derivatives, several displaying the same acrylate moiety on the B ring exhibited potent inhibition, with IC50 values ranging from 0.29 to 10.46 µM. A functional study of the most potent of these compounds, designated 6b, revealed that it significantly suppressed the transcriptional expression of inflammatory factor IL-1ß in lipopolysaccharide-induced RAW 264.7 macrophages, and also mildly inhibited CCL2, IL6 and TNF-α. In addition, compound 6b was found to inhibit IL-1ß released in LPS-induced BMDM cells. This study demonstrates that the inhibitory effect of 6b on LPS-stimulated inflammatory mediator production in the mouse macrophage cell line RAW 264.7 correlates with the suppression of the NF-κB and MAPK signaling pathways.

Synthesis and biological evaluation of pyranocarbazole derivatives as Anti-tumor agents.

A series of pyrano[3,2-a]carbazole alkaloids were designed and synthesized as derivatives of Girinimbine. The anticancer activities of these derivatives (3, 4a-j, 5a, 5c, 5f, 5i, 6c, 7a, 7c, 7f, 7i) against 10 cancer cell lines were studied. Among them, compounds 3 and 7i with N-methyl piperazine showed significant anticancer activity against MCF-7 cell lines with the IC50 values of 1.77 and 4.32 µM, respectively. Furthermore, their effects on altering cell morphology, inducing cell cycle arrest and apoptosis in MCF-7 cells were studied in vitro. In addition, the molecular docking study was carried out by using Discovery Studio software to predict the interactions between these derivatives and tubulin. All in all, these consequences reveal that pyranocarbazole derivatives with N-methyl piperazine can be used as potential anticancer lead compounds and provide useful points for the further optimization of pyranocarbazole alkaloids.

Magnetic Nanoparticles Functionalized with Copper Hydroxyproline Complexes as an Efficient, Recoverable, and Recyclable Nanocatalyst: Synthesis and Its Catalytic Application in a Tandem Knoevenagel-Michael Cyclocondensation Reaction.

A novel catalyst has been afforded by attaching of a Cu(proline)2 complex to magnetic nanoparticles through cheap, simple, and readily available chemicals. This catalyst was characterized by Fourier transform infrared, energy-dispersive X-ray, X-ray diffraction, vibrating-sample magnetometry, transmission electron microscopy, scanning electron microscopy, and inductively coupled plasma analyses. The catalytic activity of the Fe3O4@NH2@TCT@HProCu nanocatalyst was investigated in a green and effective synthesis of pyran derivatives in high yields by applying three-component reactions of malononitrile, dimedone, and aldehydes in ethanol. Conversion was high under optimal conditions. The obtained nanocatalyst could be easily separated from the mixture of the reaction and was recyclable nine times via a simple magnet without considerable reduction of its catalytic efficiency. Operational simplicity, high product yields, environmental friendliness, ecofriendliness, economical processing, and easy workup are the features of this methodology.

Design and synthesis of herboxidiene derivatives that potently inhibit in vitro splicing.

Herboxidiene is a potent antitumor agent that targets the SF3B subunit of the spliceosome. Herboxidiene possesses a complex structural architecture with nine stereocenters and design of potent less complex structures would be of interest as a drug lead as well as a tool for studying SF3B1 function in splicing. We investigated a number of C-6 modified herboxidiene derivatives in an effort to eliminate this stereocenter and, also to understand the importance of this functionality. The syntheses of structural variants involved a Suzuki-Miyaura cross-coupling reaction as the key step. The functionalized tetrahydrofuran core has been constructed from commercially available optically active tri-O-acetyl-d-glucal. We investigated the effect of these derivatives on splicing chemistry. The C-6 alkene derivative showed very potent splicing inhibitory activity similar to herboxidiene. Furthermore, the C-6 gem-dimethyl derivative also exhibited very potent in vitro splicing inhibitory activity comparable to herboxidiene.

Spliceostatins and Derivatives: Chemical Syntheses and Biological Properties of Potent Splicing Inhibitors.

Spliceostatins and thailanstatins are intriguing natural products due to their structural features as well as their biological significance. This family of natural products has been the subject of immense synthetic interest because they exhibit very potent cytotoxicity in representative human cancer cell lines. The cytotoxic properties of these natural products are related to their ability to inhibit spliceosomes. FR901564 and spliceostatins have been shown to inhibit spliceosomes by binding to their SF3B component. Structurally, these natural products contain two highly functionalized tetrahydropyran rings with multiple stereogenic centers joined by a diene moiety and an acyclic side chain linked with an amide bond. Total syntheses of this family of natural products led to the development of useful synthetic strategies, which enabled the synthesis of potent derivatives. The spliceosome modulating properties of spliceostatins and synthetic derivatives opened the door for understanding the underlying spliceosome mechanism as well as the development of new therapies based upon small-molecule splicing modulators. This review outlines the total synthesis of spliceostatins, synthetic studies of structural derivatives, and their bioactivity.

Quinazolinone-dihydropyrano[3,2-b]pyran hybrids as new α-glucosidase inhibitors: Design, synthesis, enzymatic inhibition, docking study and prediction of pharmacokinetic.

A series of new quinazolinone-dihydropyrano[3,2-b]pyran derivatives 10A-L were synthesized by simple chemical reactions and were investigated for inhibitory activities against α-glucosidase and α-amylase. New synthesized compounds showed high α-glucosidase inhibition effects in comparison to the standard drug acarbose and were inactive against α-amylase. Among them, the most potent compound was compound 10L (IC50 value = 40.1 ± 0.6 µM) with inhibitory activity around 18.75-fold more than acarboase (IC50 value = 750.0 ± 12.5 µM). This compound was a competitive inhibitor into α-glucosidase. Our obtained experimental results were confirmed by docking studies. Furthermore, the cytotoxicity of the most potent compounds 10L, 10G, and 10N against normal fibroblast cells and in silico druglikeness, ADME, and toxicity prediction of these compounds were also evaluated.

Synthesis, molecular modeling and biological evaluation of new benzo[4,5]thieno[3,2-b]pyran derivatives as topoisomerase I-DNA binary complex poisons.

A series of new benzo[b]thiophenes 2a-f and benzo[4,5]thieno[3,2-b]pyran derivatives 3a-f and 4a-f were synthesized and their structures were confirmed by elemental analyses and spectral data. All synthesized compounds were evaluated by the National Cancer Institute (NCI, USA) against 60 human tumor cell lines. Compounds 3a-f and 4a-f showed potent cytotoxic effects in one dose assay with mean growth inhibition ranging from 62% to 80%. Six compounds 3a, 3d, 3e, 3f, 4d and 4e were selected by NCI, USA for five dose evaluation against 60 human tumor cell lines. Compounds 3a, 3d, 3e and 3f exhibited very potent and broad spectrum cytotoxicity against almost all cancer cell lines with mean concentration that yield 50% growth inhibition (MG-MID GI50) of 0.1-0.58 µM and mean concentration that produce 100% growth inhibition (MG-MID TGI) of 6.03-10.00 µM. Compounds 4d and 4e exhibited very potent and selective cytotoxic activity against MDA-MB-435 subpanel (melanoma cancer) with GI50 of 0.45 µM and 0.59 µM, respectively. The mechanism of antiproliferative activity was determined for the most active compounds 3a, 3d, 3e, 3f, 4d, and 4evia measuring their half maximal inhibitory concentration (IC50) against topoisomerase I enzyme at different concentrations. Compounds 3a and 3e exhibited excellent activity compared with reference drugs with IC50 of 0.295 µM and 0.219 µM, respectively. Plasmid DNA nicking assay verified that these compounds are topoisomerase I poisons not suppressors. The active compound 3e induced a significant disruption in the cell cycle profile parallel to its effect on apoptosis induction.

Efficient biogenesis of Cu2O nanoparticles using extract of Camellia sinensis leaf: Evaluation of catalytic, cytotoxicity, antioxidant, and anti-human ovarian cancer properties.

At the moment, metallic nanoparticles especially copper nanoparticles are administrated for the cure of different disorders, such as tumor and cancer. In recent years, many chemotherapeutic supplements have been formulated by copper nanoparticles. In the present study, copper nanoparticles were prepared and synthesized in aqueous medium using Camellia sinensis leaf extract. The as-prepared Cu2O nanoparticles was thoroughly characterized using XRD, FT-IR, FESEM, EDX, TEM and X-ray elemental mapping techniques. The as-synthesized Cu2O/C. sinensis NPs applied as novel nanocatalyst for the synthesis of annulated fused pyrano[2,3-d]pyrimidinones via a one-pot, three-component condensation of a barbituric acid, aromatic aldehydes, and malonitrile or ethylcyanoacetate under mild condition at 25 °C. Main properties of this facile method are the involves an easy work-up procedure, avoidance of hazardous or polluting chemicals, significant yields under mild conditions, and one-pot reaction. We assessed the anti-human ovarian cancer potentials of these nanoparticles against Caov-3, SW-626, and SK-OV-3 cell lines. For investigating the antioxidant activities of CuCl2⋅2H2O, C. sinensis, and copper nanoparticles, the DPPH free radical test was used. For the determining of anti-human ovarian cancer properties of CuCl2⋅2H2O, Camellia sinensis leaf aqueous extract, copper nanoparticles, and Carboplatin (Standard positive control), MTT assay was used on normal (HUVECs) and human ovarian cancer (Caov-3, SW-626, and SK-OV-3) cell lines. Copper nanoparticles had high cell death and anti-human ovarian cancer properties against Caov-3, SW-626, and SK-OV-3 cell lines. Among the above cell lines, the best result was gained in the cell line of SW-626. According to the above findings, it looks copper nanoparticles green-synthesized by Camellia sinensis leaf aqueous extract have the potential to be used as a chemotherapeutic material for human ovarian cancers.

Development of 2'-aminospiro [pyrano[3,2-c]quinoline]-3'-carbonitrile derivatives as non-ATP competitive Src kinase inhibitors that suppress breast cancer cell migration and proliferation.

Src kinase activity controls diverse cellular functions, including cell growth, migration, adhesion, and survival. It is de-regulated in several cancers, including breast cancer, where it is highly expressed and phosphorylated. Thus, targeting Src by a small molecule is a feasible strategy for managing different breast cancer types. Several Src kinase inhibitors are available, including the FDA-approved drug (dasatinib). However, they are primarily ATP-competitive inhibitors that have been reported to lack specificity towards Src. We have a long-time interest in discovering protein kinase inhibitors that are non-competitive for ATP. In this project, three groups of 2'-aminospiro[pyrano[3,2-c]quinoline]-3'-carbonitrile derivatives were designed and synthesized, hypothesizing that small molecules with a spiro scaffold appended to a pyrano[3,2-c]quinoline analog could act as non-ATP competitive Src kinase inhibitors. 3b, 3c, and 3d inhibited Src kinase activity with IC50s of 4.9, 5.9, and 0.9 µM, respectively. At the same time, they did not impact the MDM2/p53 interaction in HEK293 cells, which has been reported to be affected by some spirocyclic compounds. 25 µM of 3b, 3c, or 3d did not inhibit the kinase activity of ERK2, JNK1, or p38-alpha in an in-vitro kinase assay. Steady-state kinetic studies for the effect of 3d on the ability of recombinant Src to phosphorylate its substrate (Srctide) revealed a non-ATP competitive inhibition mechanism. 1.6 µM of 3d was enough to diminish Src, Fak, and paxillin phosphorylation in the breast cancer cell lines MDA-MB-231 and MCF7. In the NCI screening, 3d induced broad tumor cytotoxicity for the NCI-60 cell lines, including all the breast cancer cell lines. The potency of 3b, 3c, and 3d to inhibit migration, proliferation, and colony formation of MDA-MB-231 and proliferation of MCF7 cells correlates with their potency to suppress Src kinase activity in the same cell line. Noticeably, the cell growth suppression and apoptosis induction in the tested cell lines can be attributed to the ability of the new derivatives to suppress the ERK and Akt survival pathways downstream of Src.

Synthesis, DFT calculation, pharmacological evaluation, and catalytic application in the synthesis of diverse pyrano[2,3-c]pyrazole derivatives.

Pyranopyrazole and its derivatives are classified to be a pharmacologically significant active scaffold for almost all modes of biological activities. In this work, An efficient, green, and facile three-component reaction for preparing pyrano[2,3-c]pyrazole derivatives via the condensation reaction of 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one, ethyl acetoacetate, and malononitrile in the presence of ZnO Nanoparticle. The products are produced with high yields and in shorter reaction times. It also is mild, safe, green, and environmentally friendly. The geometric parameters such as dipole moment, bond length, dihedral angles, total energy, heat of formation, atomic charges and energies at a highly accurate for prepared compounds were computed by Denisty Functional Theory along with the B3LYP functional. The newly synthesized compounds were screened for their anti-inflammatory and antioxidant activity. Some of the tested compounds displayed promising activities. The newly prepared compounds were found to be potent towards the antioxidant activity. Results indicated that compounds 11 and 12 exhibited significant (p ≥ 0.05) in vitro total antioxidant activity as 44.93 ± 0.15 and 39.60 ± 0.10 U/ML, respectively higher than standard ascorbic acid (29.40 ± 0.62).