Synthesis of New Benzoxazinone,Quinazolinone, and Pyrazoloquinazolinone Derivatives and Evaluation of Their Cytotoxic Activity Against Human Breast Cancer Cells

Synthesis of 2‐[3‐(3,4‐dichlorophenyl)‐3‐oxoprop‐1‐enyl]‐4H‐benzo[3,1]oxazin‐4‐one 2 as a precursor to synthesize quinazolinones 5 , 7 pyrazolylquinazolinones, 4 , 12 , 13 , 14 , 16 benzothiazine thione 10 , benzene derivative 3 pyrroloquinazolinone 6 , benzoimidazoquinazolinone 8 , and pyrazolotriazepinoquinazolinone 15 . The structures of the newly synthesized compounds were established by their elemental analyses and spectral data. Most of the synthesized compounds exhibited high antitumor and cytotoxic activity against human breast cancer cells.     

Synthesis of novel [1,2,3]triazolo[4′,5′:3,4]pyrrolo[1,2-a]thieno[2,3-d] pyrimidines: Potent EGFR targeting anti-breast cancer agents

In this study, we designed and synthesized several novel fused [1,2,3]triazolo [4′,5′:3,4]pyrrolo[1,2-a]thieno[2,3-d]pyrimidine derivatives using in a single [3 + 2] reaction cycloaddition reaction of 3-(3-iodoprop-2-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one ( 4 ) followed by C-C bond coupling with various aryl azides in a PEG-400 medium. All of the newly synthesized compounds were evaluated in vitro for EGFR kinase inhibitory action as well as anti-breast cancer activity against MDA-MB-231 and MCF-7 breast cancer cell lines. When compared to the reference molecule, erlotinib, the majority of the compounds demonstrated adequate efficacy. The most promising compounds, 5g and 5i , demonstrated excellent anticancer activity against both cancer cell lines, with IC₅₀ values ranging from 04.17 ± 0.55 to 8.65 ± 0.89 μM, respectively, as well as excellent kinase inhibitory activities (EGFR: IC₅₀ = 0.467 ± 0.063 and 0.412 ± 0.081 μM). The in silico studies of five potent compounds 5f , 5g , 5h , 5i , and 5k were also carried out to identify the interactions against the EGFR receptor and found that the energy calculations were covenant with the obtained IC₅₀ values.     

Design,Synthesis, and Anticancer Activity of Novel Fused Purine Analogues

6‐Mercaptopurine has been utilized for the synthesis of various fused purine analogues through different chemical reactions to yield [1,4]thiazino[4,3,2‐gh ]purines 2, 3, 10a,b, 14 , (8‐oxo‐[1,4]thiazino[4,3,2‐gh ]purin‐7(8H )‐ylidene) acetate 4 , [1,4]thiazepino[4,3,2‐gh ]purine 6 , thiazolo[3,4,5‐gh ]purine 7 , imidazo[1,5,4‐gh ]purin‐5‐amine 8 , 5‐methylimidazo[1,5,4‐gh ]purine 9 , [1,2,4]triazino[4,3‐i ]purines 16, 18, 21 , [1,2,4]triazino[4,5,6‐gh ]purine 20 , 5‐methyl‐2‐(7H ‐purin‐6‐yl)‐1H ‐pyrazol‐3(2H )‐one 22 , [1,2,4]triazolo[4,3‐i ]purine 23 , [1,2,5]triazepino[5,4,3‐gh ]purine 24 , and ethyl 6‐(2‐(ethoxycarbonyl)hydrazinyl)‐9H ‐purine‐9‐carboxylate 26 . Seventeen of the newly synthesized compounds were selected by the NCI, Maryland, USA, and were tested for their anticancer activity in an initial single high dose in the full NCI 60 cell line panel among which [1,4]thiazino[4,3,2‐gh ]purine‐7,8‐dione 2 , 7‐benzyl‐[1,4]thiazino[4,3,2‐gh ]purine 10b , and 3‐(2,4‐dimethoxyphenyl)‐7H ‐[1,2,4]triazolo[4,3‐i]purine 23 were found to possess very potent anticancer activity against most of the cancer cell lines.     

Conformationally restricted tricyclic analogues of lipophilic pyrido[2,3‐d]pyrimidine antifolates

The effect of conformational restriction of the C9‐N10 bridge on inhibitory potency and selectivity of trimetrexate against dihydrofolate reductase, was studied. Specifically three nonclassical tricyclic 1,3‐diamino‐8‐(3′,4′,5′‐trimethoxybenzyl)‐7,9‐dihydro‐pyrrolo[3,4‐c]pyrido[2,3‐d]pyrimidin‐6(5H,8H)‐one ( 4 ), 1,3‐diamino‐8‐(3′,4′,5′‐trimethoxybenzyl)‐9‐hydro‐pyrrolo[3,4‐c]pyrido[2,3‐d]pyrimidin‐6‐(8H)‐one ( 5 ) and 1,3‐diamino‐(8H)‐(3′,4′,5′‐trimethoxybenzyl)‐7,9‐dihydro‐pyrrolo[3,4‐c]pyrido[2,3‐d]pyrimidine ( 7 ) antifolates were synthesized. The tricyclic analogues 4 and 5 were obtained via the regiospecific cyclo‐condensation of the β‐keto ester 17 with 2,4,6‐triaminopyrimidine. The analogue 7 was obtained via reduction of the lactam 4 with borane in tetrahydrofuran. Compounds 4, 5 and 7 were evaluated as inhibitors of dihydrofolate reductase from Pneumocystis carinii, Toxoplasma gondii and rat liver. All three compounds were more selective than trimetrexate against Pneumocystis carinii dihydrofolate reductase and significantly more selective than trimetrexate against Toxoplasma gondii dihydrofolate reductase compared with rat liver dihydrofolate reductase.     

Novel Pyrano[2,3‐d]thiazole and Thiazolo[4,5‐b]pyridine Derivatives: One‐pot Three‐component Synthesis and Biological Evaluation as Anticancer Agents,c‐Met,and Pim‐1 Kinase Inhibitors

Preparation of pyrano[2,3‐d]thiazole and thiazolo[4,5‐b]pyridine derivatives through multicomponent reactions (MCRs) was achieved by the reaction of 2‐(2‐amino‐4,5,6,7‐tetrahydrobenzo[b]thiophen‐3‐yl)thiazol‐4(5H)‐one with various active methylene reagents such as ethyl cyanoacetate or malononitrile in basic conditions containing diverse aromatic aldehyde. Furthermore, this study aims to evaluate the in vitro cytotoxic activity of the synthetic compounds against six cancer cell lines, and all the prepared compounds revealed valuable activity compared with the CHS‐828, which is the 2‐[6‐(4‐chlorophenoxy)hexyl]‐1‐cyano‐3‐pyridin‐4‐ylguanidine as the standard drug. Some of the pyrano[2,3‐d]thiazole and thiazolo[4,5‐b]pyridine derivatives showed the highest antitumor activity towards the six cancer cell lines. Moreover, (c‐Met) enzymatic activity of the most potent compounds showed that compounds 3b 2‐(2‐amino‐4,5,6,7 tetrahydrobenzo[b]thiophen‐3‐yl)‐5‐hydroxy‐7‐(2‐hydroxy‐phenyl)‐7H‐pyrano[2,3‐d]thiazole‐6 carbonitrile and 5e 2‐(2‐amino‐4,5,6,7‐tetrahydrobenzo[b]thiophen‐3‐yl)‐5‐hydroxy‐7‐phenyl‐4,7‐dihydrothiazolo[4,5‐b]pyridine‐6‐carbonitrile were with higher activities than foretinib. Three compounds were selected to examine their Pim‐1 kinase where compounds 3b and 7b showed the highest inhibitions.     

Synthesis and Antibacterial Activity of Some New 2,5‐Disubstituted‐1,3,4‐oxadiazole Derivatives

Synthesis of some new oxadiazole derivatives starting from 1,2,3-benzo[d]triazole-1-acetic hydrazide (1) is described. The target compounds 2-(N-substituted-aminocarbonylmethylthio)-5-(1,2,3-benzo[d]triazol-1-ylmethyl)- 1,3,4-oxadiazole (4a—4i) and 2-[2-(N-substituted-aminocarbonyl)ethylthio]-5-(1,2,3-benzo[d]triazol-1-ylmethyl)- 1,3,4-oxadiazole (5a—5i) were obtained in good yields via cyclisation of 1 and subjected to antibacterial activity test against pathogenic bacteria. The halogen containing mono- and di-substituted derivatives showed excellent antibacterial activity compared to other analogues.     

The synthesis and cytotoxic evaluation of a series of benzodioxole substituted titanocenes

Using 6‐benzo[1,3]dioxolefulvene ( 1a ), a series of benzodioxole substituted titanocenes was synthesized. The benzyl‐substituted titanocene bis[(benzo[1,3]dioxole)‐5‐methylcyclopentadienyl] titanium (IV) dichloride ( 2a ) was synthesized from the reaction of Super Hydride with 1a . An X‐ray determined crystal structure was obtained for 2a . The ansa‐titanocene {1,2‐di(cyclopentadienyl)‐1,2‐di‐(benzo[1,3]dioxole)‐ethanediyl} titanium(IV) dichloride ( 2b ) was synthesized by reductive dimerisation of 1a with titanium dichloride. The diarylmethyl substituted titanocene bis(di‐(benzo[1,3]dioxole)‐5‐methylcyclopentadienyl) titanium(IV) dichloride ( 2c ) was synthesized by reacting 1a with the para‐lithiated benzodioxole followed by transmetallation with titanium tetrachloride. When titanocenes 2a–c were tested against pig kidney (LLC‐PK) cells inhibitory concentrations (IC₅₀) of 2.8 × 10^?4, 1.6 × 10^?4 and 7.6 × 10^?5 M , respectively, were observed. These values represent improved cytotoxicity against LLC‐PK, when compared with unsubstituted titanocene dichloride, but are not as impressive as values obtained for titanocenes previously synthesized using the above methods. Copyright © 2006 John Wiley & Sons, Ltd.     

An Efficient Synthesis of Chromeno[4,3‐d]isoxazolo[5,4‐b]pyridin‐6‐one Derivatives

A series of chromeno[4,3‐d]isoxazolo[5,4‐b]pyridin‐6‐one derivatives were easily and efficiently synthesized by the reaction of 3‐acyl‐2H‐chromen‐2‐ones with isoxazol‐5‐amine in acetic acid. Some synthesized compounds were evaluated for their antiproliferative properties in vitro against cancer cells, and these compounds were found to have some activities.     

Synthesis and Anticancer Evaluation of Some Novel Thiophene,Thieno[3,2‐d]pyrimidine,Thieno[3,2‐b]pyridine,and Thieno[3,2‐e][1,4]oxazepine Derivatives Containing Benzothiazole Moiety

In an attempt to establish novel candidate with promising anticancer activity, two derivatives of (benzo[d]thiazol‐2‐yl)thiophene backbone 1 and 14 were synthesized, and they further reacted with various chemical reagents to afford the corresponding substituted thiophene derivatives 6 , 8 , 10 , 15 , 17 , and 20 , thieno[3,2‐d]pyrimidine derivatives 2 – 5 , 7 , 9 , 16 , 21 , 23 , and 24 , thieno[3,2‐b]pyridine derivatives 11 – 13 , and thieno[3,2‐e][1,4]oxazepine derivative 18 . Structures of prepared compounds were affirmed via spectral and elemental data. Among the obtained compounds, seven derivatives 2 , 3 , 4 , 5 , 11 , 12 , and 13 were chosen by National Cancer Institute, USA. Such compounds were screened for their antitumor activity versus 60 cancer cell lines in one‐dose (10 μmol) screening assay. The outcomes showed that all selected compounds exhibited moderate to high anticancer activity towards many cancer cell lines among which compounds 5 and 11 exerted potent antitumor activity against numerous malignant growth cell lines particularly Ovarian Cancer IGROV1.     

Studies on the chemical transformations of rotenoids. 6 Synthesis and antitumor‐promoting activity of benzofuro[2,3‐d]pyridazines fused with 1,2,4‐triazole, 1,2,4‐triazine and 1,2,4‐triazepine

[1]Benzofuro[2,3‐d]pyridazines fused with 1,2,4‐triazole ( 6 and 7 ), 1,2,4‐triazine ( 8–10 ) and 1,2,4‐tri‐azepine (12) were prepared by the ring closure of 4‐hydrazino‐[1]benzofuro[2,3‐d]pyridazine ( 5 ), derived from naturally occurring rotenone. Compounds ( la and lb ) exhibited significant inhibitory activity against 12‐O‐tetradecanoylphorbol 13‐acetate (TPA)‐induced Epstein‐Barr virus early antigen (EBA‐EA) activation in Raji cells. In contrast, the fused [1]benzofuro[2,3‐d]pyridazines except 6c and 8 were quite inactive.     

Bridgehead Bicyclo[4.4.0]boron Heterocycles: A One‐Pot Four‐Component Synthesis of Dibenzo[e,i][1,3,7,2]oxadiazaborecin‐8(7H)‐ones

A one‐pot four‐component synthesis of 6‐aryl‐6H‐dibenzo[e,i][1,3,7,2]oxadiazaborecin‐8(7H)‐ones is described. Heating a mixture of isatoic anhydride and a benzylamine afforded the corresponding anthranilamide derivative, which was condensed with a 2‐hydroxybenzaldehyde and an arylboronic acid under solvent‐free conditions to produce bridgehead bicyclo[4.4.0]‐boron heterocycles in good to excellent yields. Single‐crystal X‐ray analysis conclusively confirms the structures of the obtained bridgehead bicyclic 6–6 heterocyclic compounds.     

Indoloquinazoline Alkaloids from Araliopsis tabouensis

Three new indoloquinazolidine‐type alkaloids, 8,13‐dihydro‐2‐methoxyindolo[2′,3′: 3,4]pyrido[2,1‐b]quinazolin‐5(7H)‐one ( 1 ), 8,13‐dihydro‐2‐methoxy‐13‐methylindolo[2′,3′: 3,4]pyrido[2,1‐b]quinazolin‐5(7H)‐one ( 2 ), and 5,8,13,14‐tetrahydro‐2‐methoxy‐14‐methyl‐5‐oxo‐7H‐indolo[2′,3′: 3,4]pyrido[2,1‐b]quinazolim‐6‐iun chloride ( 3 ) were isolated from Araliopsis tabouensis, together with three known compounds. The structures of the new compounds were determined primarily from 1D‐ and 2D‐NMR analysis. The antimalarial activities of compounds 1 – 5 were evaluated against Plasmodium falciparum D6 and W2 clones. The IC₅₀ values in antimalarial bioassay for compounds 2 – 5 varied from 1.8 to 4.7 μg/ml.     

Design,synthesis, pharmacological evaluation and DNA interaction studies of binuclear Pt(II) complexes with pyrazolo[1,5‐a]pyrimidine scaffold

Substituted pyrazolo[1,5‐a]pyrimidine ligands were synthesized by cyclization, using 3‐(thiophen‐2‐yl)‐1H‐pyrazol‐5‐amine with substituted enones (3‐phenyl‐1‐(pyridin‐2‐yl)prop‐2‐en‐1‐one) in presence of KOH and DMF as solvent to form cyclic aromatic compounds. The substituted pyrazolo[1,5‐a] pyrimidine based binuclear Pt^II complexes containing neutral tetradentated ligands have general formula [Pt₂(5a–5f)Cl₄], (where, (5a ‐5f) = pyrazolo[1,5‐a] pyrimidine ligand). This compounds were characterized by physicochemical and spectroscopic method like elemental analyses, UV‐Visible, FT‐IR, EDX, TGA, molar conductivity, magnetic susceptibility measurements, mass spectroscopy, ¹H and ¹³C NMR method. The square planar geometry was predicted by electronic spectral study. All Pt^II compounds were evaluated by antimicrobial assay, in vitro brine shrimp assay, in vivo cellular level bioassay using S. Pombe cells and anti‐tuberculosis study. LC₅₀ (50% lethal concentration) values of compounds are observed between 6.450 ‐ 102.07 μg/mL. UV‐vis absorption titration, competitive displacement assay, molecular docking and viscosity measurement were carried out to examine the binding type and binding strength of complexes. The binding studies suggest partial intercalative binding mode of the complexes and the observed binding constant (K_b) values are found in the order of 6d > 6b > 6c > 6a > 6e > 6 f. The anti‐proliferative cytotoxicity of the synthesized Pt^II complexes (6a‐6f) were tested against the HCT‐116 (Human Colorectal Carcinoma) cancer cell line.     

Antimicrobial Activity of Novel Tetra‐ and Penta‐azaheterocyclic Ring Systems

A novel series of substituted [1,2,4]triazolo[4′,3′:1,2]pyrimido[4,5‐c ]benzo[f ]isoquinolin‐14(10H )‐one was synthesized from the reaction of hydrazonoyl chlorides with pyrimidine thione derivative or via oxidative cyclization of 3‐(2‐substituted‐benzylidene‐hydrazinyl)‐7,8‐dihydrobenzo[f ]pyrimido[4,5‐c ]isoquinolin‐1(2H )‐one. Also, some polyhetero‐cyclic ring systems were prepared through the reaction of 2‐dimethylaminomethylene‐3,4‐dihydro‐2H‐naphthalen‐1‐one and heterocyclic amines. The biological activity of some new products was evaluated, and the results obtained revealed that compounds 10e , 13a , and 18 showed excellent activities against the most bacteria and fungi species used.     

A Facile Synthesis of Aryl‐Substituted Hydrazono‐Pyrazolyl[1,2,4]triazolo[3,4‐b][1,3,4][thiadiazol]‐coumarin Derivatives

Some inimitable and therapeutic coumarin‐substituted fused[1,2,4]triazolo‐[3,4‐b][1,3,4]thiadizole derivatives were synthesized by the cyclocondensation reaction of 2‐oxo‐2H‐chromene‐3‐carboxylic acid ( 1 ) and 4‐amino‐5‐hydrazinyl‐4H‐[1,2,4]‐triazole‐3‐thiol ( 2 ) by using phosphorous oxychloride as a cyclizing agent. This cyclized intermediate 3‐(3‐hydrazino‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazol‐6‐yl)‐chromen‐2‐one ( 3 ) later condensation with various ethyl 2‐(2‐arylhydrazono)‐3‐oxobutanoates ( 4 ) in NaOAc/MeOH under reflux conditions afforded the corresponding new series of aryl‐substituted hydrazono‐pyrazolyl‐[1,2,4]triazolo[3,4‐b][1,3,4][thiadiazol]‐coumarin derivatives ( 5 ) in good to excellent yields. The structures of newly synthesized compounds were established on the basis of elemental analysis, IR, ¹H NMR and mass spectroscopic studies.     

Synthesis of Pyridotriazolopyrimidines as Antitumor Agents

2‐Hydrazino‐5,7‐di‐p‐tolylpyrido[2,3‐d ]pyrimidin‐4(3H )‐one ( 4 ) was prepared and condensed with different aldehydes 5a , 5b , 5c , 5d , 5e , 5f , 5g to give the corresponding hydrazone derivatives 6a , 6b , 6c , 6d , 6e , 6f , 6g . Oxidative cyclization of the latter compounds 6a , 6b , 6c , 6d , 6e , 6f , 6g gave the corresponding pyrido[2,3‐d ][1,2,4]triazolo[4,3‐a ]pyrimidin‐5(1H )‐ones 7a , 7b , 7c , 7d , 7e , 7f , 7g . Furthermore, compound 4 reacted with benzoyl chloride, triethyl orthoformate, acetyl chloride, ethyl chloroformate, and carbon disulphide in alcoholic KOH solution to afford the corresponding pyrido[2,3‐d ][1,2,4]triazolo[4,3‐a ]pyrimidinones ( 7a , 8 , 9 , 10 , 11 ). The reaction of thione 3 or its 2‐methylthio derivative 16 with hydrazonoyl halides 12a , 12b , 12c , 12d , 12e , 12f , 12g , 12h , 12i , 12j , 12k , 12l , 12m yielded the corresponding pyrido[2,3‐d ][1,2,4]triazolo[4,3‐a ]pyrimidinones 15a , 15b , 15c , 15d , 15e , 15f , 15g , 15h , 15i , 15j , 15k , 15l , 15m . The structures of all the products were confirmed by elemental and spectral analyses (¹H NMR, ¹³C NMR, IR, and MS). In addition, the anticancer activity of 20 pyridotriazolopyrimidinones against two cancer cell lines namely MCF‐7 and HepG2 was evaluated, and the results revealed that compounds 7d and 9 have promising activity , compared with doxorubicin, which used as standard reference drug.     

Facile Synthesis of Novel 3‐(4‐phenylisothiazol‐5‐yl)‐2H‐chromen‐2‐one Derivatives as Potential Anticancer Agents

A series of 3‐(4‐phenylisothiazol‐5‐yl)‐2H‐chromen‐2‐one ( 6a – l ) derivatives has been efficiently synthesized by straightforward sequential reactions. Tandem Vilsmeier Hack reaction/cyclization/bromination/Suzuki cross‐coupling reactions were successfully applied to the preparation of title compounds in good‐to‐high yields. In the synthetic sequences, 3‐chloro‐3‐(2‐oxo‐2H‐chromen‐3‐yl)acrylaldehydes ( 2 ) were found to react with ammonium thiocyanate to yield the corresponding 3‐(isothiazol‐5‐yl)‐2H‐chromen‐2‐ones ( 3 ). These derivatives were brominated with N‐bromo succinamide to yield the corresponding regioselective 3‐(4‐bromoisothiazol‐5‐yl)‐2H‐chromen‐2‐one ( 4 ). Finally, compound 4 was treated with various phenyl/pyrazole/7H –pyrrolo[2,3‐d]pyrimidinyl boronic acids 5a – l in the presence of K₂CO₃ and Pd catalyst in dimethylformamide to yield the corresponding title derivatives 6a – l . All the synthesized compounds were characterized by analytical and spectral studies. All the final compounds were screened against different cancer cell lines (A549, PC3, SKOV3, and B16F10), and among these compounds, 6b , 6g , 6h , and 6l displayed moderate cytotoxic activity against the tested cell lines.     

Synthesis and Fungicidal Activity of (E)‐5‐[1‐(2‐Oxo‐1‐oxaspiro[4,5]dec/non‐3‐en‐3‐yl)ethylidene]‐2‐aminoimidazolin‐4‐one Derivatives

The novel fungicidal agents, (E )‐5‐[1‐(2‐oxo‐1‐oxaspiro[4,5]dec/non‐3‐en‐3‐yl)ethylidene]‐2‐aminoimidazolin‐ 4‐one derivatives, were designed and synthesized in moderate to excellent yields in four steps using α ‐hydroxyketone and diketene as raw materials and characterized by HR‐ESI‐MS , ¹H NMR and X‐ray diffraction. The preliminary bioassay showed that some of these compounds, such as 5e , 6a , 6e , and 7 h exhibit 87.8%, 91.3%, 89.9% and 87.8% inhibition rates against Sclerotinia scleotiorum , 3b , 3c , 4c and 7 h exhibit 96.4%, 92.5%, 90.3% and 76.9% inhibition rates against Phytophthora capsici at the concentration of 50 µg/mL , respectively. These compounds exhibited significant fungicidal activities against S. scleotiorum and P. capsici with EC₅₀ values of 2.56–11.60 µg/mL , and compounds 6e and 7 h exhibited weak inhibition against the spore germination of S. scleotiorum , while the spore germination of P. capsici was strongly inhibited by compound 7 h solution. Scanning electron microscopy (SEM ) and transmission electron microscopy (TEM ) observation indicated that compound 7 h had a significant impact on the structure and function of the hyphal cell wall of P. capsici mycelium.     

Insecticidal Evaluation and [4+2] Aza‐Diels‐Alder Synthesis of 3,7‐Diaryl‐6,7‐dihydro‐5H‐6‐substituted Thiazolo[3,2‐a]pyrimidin‐5‐ones Under Coupled Ultrasonic Irradiation and PTC

A series of 3,7‐diaryl‐6,7‐dihydro‐5H‐6‐substituted‐thiazolo[3,2‐a]pyrimidin‐5‐ones ( 3a , 3b , 3c , 3d , 3e , 3f , 3g , 3h , 3i , 3j ) were synthesized by the [4+2] cycloaddition reaction of 2‐arylideneamino‐4‐arylthiazoles (2a–j) with in situ generated monosubstituted ketenes under PTC conditions coupled with ultrasonication in good to excellent yields. All the synthesized compounds were characterized on the basis of their spectral (IR, PMR, and Mass) and analytical data. The synthesized compounds were also screened for their insecticidal activity against Helicoverpa armigera and some of them showed promising activity.