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Substituted-6-methyl-1-thioxo-1,2-dihydro-3H-furo[3,2-g]pyrimido[1,6-a]quinazolin-3-ones (5a,b) were synthesized from condensation of visnagenone (2a) or khellinone (2b) with 6-amino-thiouracil (3) in dimethylformamide or refluxing of (4a) or (4b) in dimethylformamide. Hence, compounds (5a,b) were used as the starting materials for preparing many new heterocyclic compounds such as; furo[3,2-g]pyrimido[1,6-a]quinazoline (6a,b), furo[3,2-g]thiazolo[20,30:2,3] pyrimido[1,6-a]quinazolinone (7a,b), substituted-benzylidene-furo[3,2-g]thiazolo[20,30:2,3]pyrimido [1,6-a]quinazoline-3,5-dione (8a-f), 3-oxo-furo[3,2-g]pyrimido[1,6-a]quinazoline-pentane-2,4-dione (9a,b), 1-(pyrazole)-furo[3,2-g]pyrimido[1,6-a]quinazolinone (10a,b), 2-(oxo or thioxo)-pyrimidinefuro[ 3,2-g]pyrimido[1,6-a]quinazolinone (11a-d), 1-(methylthio)-furo[3,2-g]pyrimido[1,6-a] quinazolinone (12a,b), 1-(methyl-sulfonyl)-furo[3,2-g]pyrimido[1,6-a]quinazolinone (13a,b) and 6-methyl-1-((piperazine) or morpholino)-3H-furo[3,2-g]pyrimido[1,6-a]quinazolin-3-one (14a-d). The structures of the prepared compounds were elucidated on the basis of spectral data (IR, 1H-NMR, 13C-NMR, MS) and elemental analysis. Antimicrobial activity was evaluated for the synthesized compounds against Gram-positive, Gram-negative bacteria and fungi. The new compounds, furothiazolo pyrimido quinazolines 8a-f and 11a-d displayed results excellent for growth inhibition of bacteria and fungi.

The structural analysis of khellinone and visnaginone indicated the planarity of the benzo[b]furan ring system. The oxygen or carbon atoms of the substituents, -OH, -OCH3, and -C(=O)CH3, are nearly coplanar with the aromatic ring. The molecular conformation is stabilized by the intramolecular O-H..O hydrogen bond formed between the ortho-substituted hydroxyl and acetyl groups. The intermolecular contacts present in the crystal structure are the C-H..O and C-H..π interactions and the π..π stacking. The energy surface for the internal rotation about the Csp2-O/C bonds in the khellinone and visnaginone molecules has been explored by quantum-chemical calculations. The density functional theory (DFT) methods yielded three stable conformers of khellinone and two of visnaginone obtained by a rotation of the methoxy group about the C4sp2-OCH3 bond. The most stable conformation in the gas phase is consistent with the stereochemistry of the molecules adopted in the solid. The secondary minima conformers have energies higher by 0.3-1.8 kcal/mol. The energy of the intramolecular O-H..O interactions, present in the molecular structure of all stable conformers, is around 18 kcal/mol at the DFT level. A complete and reliable assignment of the bands in the IR and Raman spectra of both compounds has been performed.

Abstract: A series of novel quinoxaline, pyrimidine, and pyrazole furochromone derivatives were synthesized for the first time. These derivatives were prepared under mild conditions using a stepwise efficient methodology. The developed protocol led to the synthesis of furochromone derivatives in moderate to good yields (60–75%). The structures of the prepared derivatives were identified using several spectroscopic techniques including IR, NMR, and mass spectrometry. The cytotoxic activity of the synthesized derivatives was evaluated using in vitro Ehrlich ascites assay. Pyrazolobenzofurans exhibited the most potent effect suggesting the importance of pyrazole nucleus for the cytotoxic activity. Graphical abstract: [Figure not available: see fulltext.].

A new series of potent antitumor and antiviral benzofuran derivatives was synthesized by the reaction of the furochromone-6-carboxaldehydes 1 and 2 with different heterocyclic amines to yield the benzofuran-5-carbonyl derivatives 4-11. The synthesized compounds 1, 3-11 were tested against twelve different human cancer cell lines and all of the compounds were more potent than the comparative standards. The HIV inhibitory activity of the tested compounds 1, 3-11 showed that they have higher potency than Atevirdine. Moreover, compound 6 was significantly potent with wider therapeutic index. The HIV-1 RT inhibitory activity showed that compounds 10, 11, 3 and 4 were notably potent but with lower therapeutic index than Atevirdine. The HCV NS3-4A protease inhibitor activity of the tested compounds revealed that they have weaker potency and less therapeutic index than VX-950, although compounds 1, 4, 9 and 6, respectively exhibited significant activity.

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In continuation of our work concerning the relation between the anticancer and anti-vascular endothelial growth factor receptor (anti-VEGFR-2) activity of some synthesized compounds, we hereby designed and prepared three new series of furochromone and benzofuran derivatives (carbonitriles, sulfonyl hydrazides and imides). The prepared compounds were evaluated for their in vitro VEGFR-2 inhibitory activity, their cytotoxicity on fifteen human cancer cell lines and their in vivo antiprostate cancer activity. The highest anti-VEGFR-2 activity was demonstrated by 6-acetyl-4-methoxy-7-methyl-5H-furo[3,2-g]chromen-5-one (3), which exhibited the same IC50 value as the reference drug sorafenib (2.00 × 10-3 μM). On the other hand, most of the synthesized compounds showed potent cytotoxicity against most of the tested cell lines, in particular, the carbonitrile series (4a,b and 5a,d) which exhibited the best activity with IC50 values ranging from 3.56 × 10-13 to 4.89 × 10-7 μM. Moreover, the imide series (15-17) showed the most significant in vivo antiprostate cancer activity. An in silico GOLD molecular docking study has been done to explore the binding mode of interaction of the furochromone and benzofuran derivatives to VEGFR-2 kinase, and to reveal the correlation between IC50 (μM) of the enzymatic inhibition of VEGFR-2 kinase and the GoldScore fitness for further therapeutic application. This journal is

Two new series of coumarin and benzofuran derivatives were designed, synthesized, and assessed for their in vitro and in vivo antitumor activities against breast cancer. Compounds 8, 9, 14, 15, and 17 exhibited the best antiproliferative activities (IC50: 0.07?2.94 μM) against the MCF-7 cell line, compared with lapatinib (IC50: 4.69 μM). Compound 14, with the most potent cytotoxic activity against MCF-7 cells, was capable of enhancing preG1 apoptosis and triggering cell cycle arrest at the G2/M phase. The kinase inhibitory activity of compound 14 against a panel of 22 kinases was examined to reveal multikinase inhibition within ?39% to ?97%. Furthermore, compound 14 exhibited potent in vivo Ehrlich (mammary adenocarcinoma) tumor regression, positive caspase-3, and negative EGFR immunoreaction, and was capable of elevating the catalase level. The physicochemical properties and pharmacokinetic parameters of compound 14 were investigated in silico for its druglikeness.

Background: Previous and recent scientific research has shown that triazolopyrimidine and furochromones have a wide range of pharmacological activities for the treatment of numerous diseases, including anticancer, antiviral, anti-depressant, anti-microbial, anti-inflammatory, and analgesic activities. Objective: Preparation of new drugs derived from a natural furochromones as (1-hydrazinyl or methylthio),-furopyrimidoquinazolinone, 1, 2, 4-triazolopyrimidofuroquinazolin-5-one, and quina-zoline-pyrimidofuro-quinazoline-8, 10-dione and the study of their biological activity as antimi-crobial agents. Method: A series of novel N’-furopyrimidoquinazoline-hydrazide; 1, 2, 4-triazolopyrimidofuro-quinazolin-5-one; furopyrimidoquinazolin-3-one and quinazoline-pyrimidofuroquinazoline-8, 10-dione derivatives were synthesized from substituted (methylthio)-furopyrimidoquinazolinone (3a-b) and 1-hydrazinyl-furopyrimido-quinazolinone (4a-b) as the starting material. Results: All compounds were synthesized in good yields (71-95%) in a gradually efficient system under mild condition and some of the procedures were used such as microwave oven. The new compounds have been confirmed by means of different spectroscopic methods such as IR, 1D and 2D-NMR techniques and mass spectrum. The in vitro antimicrobial activities were evaluated for the prepared compounds using many types of bacteria (Gram-positive and Gram-negative) and fungi. Conclusion: 1, 2, 4-triazolopyrimidofuroquinazolin-5-one derivatives (10a-f, 8a-b, 7a-b and 6a-d) showed the most efficient antimicrobial activities compared with the cefotaxime sodium and nys-tatin as standard drugs.

Two new series of furochromone and benzofuran derivatives were designed, synthesized and evaluated for their in vitro anticancer activity against MCF-7 and MDA231 breast cancer cell lines. Compounds 5, 6, 7, 9, 15a, 16, 17a and 18 exhibited the best antip

The reaction of cotarnine and acyl/aryl ketones in “green” solvents provides an efficient approach to an array of privileged 1,2,3,4-tetrahydroisoquinolines in excellent yields by metal-free activation of C(sp3)–H bonds. This one-pot procedure takes place under base-free conditions at room temperature, and tolerates a wide range of functionalities. The reaction is highly chemoselective, can be performed on a multi-gram scale, and pure products are isolated by simple filtration without workup. Interestingly, the complementary two-step procedure from cotarnine halide salts gives the Mannich products in good yields. The scope was elaborated to 9-bromocotarnine salts to access a range of 9-bromonoscapine-derived analogues. The methodology has been developed considering the structural similarity of cotarnine derivatives to noscapinoids, which represent an emerging class of microtubule-modulating anticancer agents.

Various flavonoid scaffold based derivatives viz furochalcones (3a-e, 6a-d and 9a-d), furoflavones (10a-d, 11a-d, 12a-d, 18a&b), flavones (21a-d), furoaurones (13a,b, 14a-d and 15a-d) and 7-styrylfurochromones (22a-d and 25a-e) were designed and synthesiz

New series of furosalicylic acids 3a - c, furosalicylanilides 6a - n, furobenzoxazines 8a - f, 1-benzofuran- 3-arylprop-2-en-1-ones 12a,b, 6-(aryl-3-oxoprop-1-enyl)-4H-chromen-4-ones 16a - c and 6-[6-aryl-2-thioxo- 2,5-dihydropyrimidin-4-yl]-4H-chromen-4-ones 17a - c were synthesized. Anti-inflammatory activity evaluation was performed using carrageenan-induced paw edema model in rats and prostaglandin E2 (PGE2) synthesis inhibition activity. Some of the tested compounds revealed comparable activity with less ulcerogenic effect than Diclofenac at a dose 100 mg/kg. All the synthesized compounds were docked on the active site of cyclooxygenase-2 (COX-2) enzyme and most of them showed good interactions with the amino acids of the active site comparable to the interactions exhibited by Diclofenac.

The reaction of nucleophilic phosphacumulene ylides with visnaginone and khellinone afforded the corresponding phosphanylidene and furochromene derivatives. Moreover, pyranochromenes were obtained from the reaction of chromene carbaldehydes with phosphacumulenes. On the other hand, the phosphanylidene-cyclobutylidenes and their dimers were produced from the reaction of furochromene carbaldehydes with the same phosphonium reagents.

Bromination of visnaginone (1) yielded the dibromo derivative (2), which upon methylation with methyl iodide gave 1-(2,7-dibromo-4,6-dimethoxybenzofuran- 5-yl) ethanone (3). Compound (3) reacted with dimethylformamide dimethylacetal to give (4). The reaction of (3) with aromatic aldehydes namely (vanillin, benzaldehyde and 3-anisaldehyde) in ammonium acetate, malononitrile and/or butyric cyanoanhydride gave the 2-amino substituted nicotinonitriles (5a-c) and the 2-hydroxyl substituted nicotinonitriles (7a-c), respectively, while in piperidine gave (E)-1-(2,7-dibromo-4,6-dimethoxybenzofuran-5-yl)-3-(substituted) prop-2-en-1-one (11a-c). (5a) was hydrolyzed with sulfuric acid on cold to give the nicotinic acid derivative (6a). When compound (3) reacted with hydrazines and aromatic amines, it gave the Schiff bases (8a,b) and (10a,b), respectively. (8b) reacted with thioglycolic acid to give the thiazolidin-4-one (9b). When (11an-c) reacted with thiourea, it gave the pyrimidine derivatives (12an-c). (11a,b) also reacted with butyric cyanoanhydride and hydroxylamine hydrochloride to give (13a,b) and (15a,b), respectively. When the carboxylate (13a) was treated with 2,4-dinitroaniline, it gave the carboxamide (14a). Compounds (11b,c) reacted with hydrazine derivatives (hydrazine hydrate and phenylhydrazine) yielding the substituted pyrazole derivatives (16b,c) and (17b,c), respectively. All the structures of the synthesized compounds were elucidated by elemental analyses and spectral data. The newly synthesized benzofuran compounds showed a strong to moderate cytotoxicity against liver HEPG2 cancer cell line compared to 5-fluorouracil and doxorubicin (the anticancer agents). Compounds (2, 6a, 13a, 14a, 16c and 17b) were the most active compounds in descending order. The synthesized compounds were also tested for their antimicrobial activity. Compound (10b) showed the highest activity against all the tested strains followed by 6, 10a, 5a, 8b and 7a in descending order.

Synthesis of furochromone, 2-phenylchromone (flavone) and benzofuran derivatives substituted with thiosemicarbazide or thiazolidin-4-one moieties were accomplished. All the newly synthesized compounds were tested for their anticonvulsant activity in both subcutaneous pentylenetetrazole induced seizures (scPTZ) and maximal electric shock induced seizures (MES) tests using valproic acid and phenytoin respectively as reference standards. The most active compounds in scPTZ model were 1c, 2b, 5a and 7e showing 100% protection at 300 mg/kg upon intraperitoneal administration. Also, the effect of pre-treatment of three of the most active compounds (1c, 2b, 5a) on 4-amino pyridine-induced lethality in mice was investigated. Pre-treatment with these compounds significantly increased the latency for clonic and tonic seizures and prevented 4-amino pyridine induced death. Hence, this provides evidence for anticonvulsant activity of these compounds, and a neuroprotective activity for them. The structure - activity relationship was studied based on the obtained data.

The voltage-gated potassium channel Kv1.3 constitutes an attractive pharmacological target for the treatment of effector memory T cell-mediated autoimmune diseases such as multiple sclerosis and psoriasis. Using 5-methoxypsoralen (5-MOP, 1), a compound isolated from Ruta graveolens, as a template we previously synthesized 5-(4-phenoxybutoxy)psoralen (PAP-1, 2) which inhibits Kv1.3 with an IC50 of 2 nM. Since PAP-1 is more than 1000-fold more potent than 5-MOP, we here investigated whether attaching a 4-phenoxybutoxy side chain to other heterocyclic systems would also produce potent Kv1.3 blockers. While 4-phenoxybutoxy-substituted quinolines, quinazolines and phenanthrenes were inactive, 4-phenoxybutoxy-substituted quinolinones, furoquinolines, coumarins or furochromones inhibited Kv1.3 with IC50s of 150 nM to 10 μM in whole-cell patch-clamp experiments. Our most potent new compound is 4-(4-phenoxybutoxy)-7H-furo[3,2-g]chromene-7-thione (73, IC50 17 nM), in which the carbonyl oxygen of PAP-1 is replaced by sulfur. Taken together, our results demonstrate that the psoralen system is a crucial part of the pharmacophore of phenoxyalkoxypsoralen-type Kv1.3 blockers.

The reactions of 2-cyanoacetohydrazide and 2′-acetyl-2- cyanoacetohydrazide with each of furobenzopyrone derivatives 1a-d and benzofuran derivatives 10a,b have been studied. The structures of the new compounds are confirmed from their elemental analyses and spectral data. Also, the antimicrobial and antiinflammatory activity of the new compounds has been evaluated.

The synthesis of 9- and 6-alkylaminomethyl furoflavones 5a, b, 9a-c, 13a, b, 15a-g and 18 from the naturally occurring chromones visnagin and khellin. Gastroprotective potency of these compounds in the ethanol damage model was determined. The results indicate that, through appropriate substitution, furoflavones can be obtained that are gastroprotective.

Phenanthrenequinone 2 and aurones 5a-h are potentially capable of undergoing an interesting photochemical reaction leading to the formation of the adducts 6a-h. The structures of the 1,4-dioxine derivatives 6a-h were firmly established on the basis of analytical data and spectroscopic evidences.