Synthesis and antitubercular evaluation of amidoalkyl dibenzofuranols and 1H-benzo[2,3]benzofuro[4,5-e][1,3]oxazin-3(2H)-ones

A new class of amidoalkyl dibenzofuranols and 1H-benzo[2,3]benzofuro[4,5-e][1,3]oxazin-3(2H)-ones was synthesized in very good yields through polyphosphoric acid supported on silica (PPA-SiO₂) catalyzed one-pot three component condensation of 2-dibenzofuranol; aromatic aldehydes and acetamide or benzamide or urea under solvent free conditions. At 125 °C the reaction led to the formation of amidoalkyl dibenzofuranols 5a-k where as at 160 °C cyclization take place to give oxazin-3(2H)-one analogues 6a-e. Screening all the 16 compounds for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB) resulted 1-((4-chlorophenyl)(2-hydroxydibenzo[b,d]furanyl)methyl)urea 5h; 1-((4-bromophenyl)(2-hydroxydibenzo[b,d]furanyl)methyl)urea 5i; 1-phenyl-1H-benzo[2,3]benzo furo[4,5-e][1,3]oxazin-3(2H)-one 6a (MIC 3.13 μg/mL) and 1-(4-chlorophenyl)-1H-benzo[2,3]benzofuro[4,5-e][1,3]oxazin-3(2H)-one 6b; 1-(4-bromophenyl)-1H-benzo[2,3]benzofuro [4,5-e][1,3]oxazin-3(2H)-one 6c (MIC 1.56 μg/mL) as most active antitubercular agents.     

Design,synthesis, and X-ray crystal structures of 2,4-diaminofuro[2,3-d]pyrimidines as multireceptor tyrosine kinase and dihydrofolate reductase inhibitors

To optimize dual receptor tyrosine kinase (RTK) and dihydrofolate reductase (DHFR) inhibition, the E- and Z-isomers of 5-[2-(2-methoxyphenyl)prop-1-en-1-yl]furo[2,3-d]pyrimidine-2,4-diamines (1a and 1b) were separated by HPLC and the X-ray crystal structures (2.0 and 1.4 Å, respectively) with mouse DHFR and NADPH as well as 1b with human DHFR (1.5 Å) were determined. The E- and Z-isomers adopt different binding modes when bound to mouse DHFR. A series of 2,4-diaminofuro[2,3-d]pyrimidines 2–13 were designed and synthesized using the X-ray crystal structures of 1a and 1b with DHFR to increase their DHFR inhibitory activity. Wittig reactions of appropriate 2-methoxyphenyl ketones with 2,4-diamino-6-chloromethyl furo[2,3-d]pyrimidine afforded the C8–C9 unsaturated compounds 2–7 and catalytic reduction gave the saturated 8–13. Homologation of the C9-methyl analog maintains DHFR inhibitory activity. In addition, inhibition of EGFR and PDGFR-β were discovered for saturated C9-homologated analogs 9 and 10 that were absent in the saturated C9-methyl analogs.     

Discovery of 4-anilino-N-methylthieno[3,2-d]pyrimidines and 4-anilino-N-methylthieno[2,3-d]pyrimidines as potent apoptosis inducers

We report the discovery of N-((benzo[d][1,3]dioxol-5-yl)methyl)-6-phenylthieno[3,2-d]pyrimidin-4-amine (2a) as an apoptosis inducer using our proprietary cell- and caspase-based ASAP HTS assay, and SAR study of HTS hit 2a which led to the discovery of 4-anilino-N-methylthieno[3,2-d]pyrimidines and 4-anilino-N-methylthieno[2,3-d]pyrimidines as potent apoptosis inducers. Compounds 5d and 5e were the most potent with EC₅₀ values of 0.008 and 0.004 μM in T47D human breast cancer cells, respectively. Compound 5d was found to be highly active in the MX-1 breast cancer model. Functionally, compounds 5d and 5e both induced apoptosis through inhibition of tubulin polymerization.     

Synthesis and biological evaluation of substituted 1,2,3-benzotriazines and pyrido[3,2-d]-1,2,3-triazines as inhibitors of vascular endothelial growth factor receptor-2

A novel series of substituted 1,2,3-benzotriazines and pyrido[3,2-d]-1,2,3-triazines were synthesized. The abilities of these compounds to inhibit the VEGFR-2 kinase activity and the proliferation of human microvascular endothelial cells (MVECs) were determined. 6-Methoxy-4-substituted-1,2,3-benzotriazines and 4-substituted-6-chloro-pyrido[3,2-d]-1,2,3-triazines have the abilities of inhibiting the VEGFR-2 kinase activity, but only the 4-substituted-6-chloro-pyrido[3,2-d]-1,2,3-triazines exhibit good growth inhibitory effects on MVECs. Compound 6-chloro-4-(3-trifluoromethylanilino)-pyrido[3,2-d][1,2,3]triazin (11d) is less half active than PTK787 to inhibit the VEGFR-2 kinase activity, but is more active than PTK787 to inhibit the growth of MVECs. The potential binding modes of 6d, 11d, and CTZ12 in complex with their putative intracellular target, VEGFR-2, were predicted using Surflex-Dock.     

Synthesis of indole-tethered [1,3,4]thiadiazolo and [1,3,4]oxadiazolo[3,2-a]pyrimidin-5-one hybrids as anti-pancreatic cancer agents

New indole-tethered [1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (8a-j) and [1,3,4]oxadiazolo[3,2-a]pyrimidin-5-one hybrids (9a-e) were synthesized using [4+2] cycloaddition reactions of functionalized 1,3-diazabuta-1,3-dienes with indole-ketenes. All molecular hybrids were structurally characterized by spectroscopic techniques (IR, NMR, and HRMS) and screened for their anti-pancreatic cancer activity in vitro. The [1,3,4]oxadiazolo[3,2-a]pyrimidin-5-one hybrids (9a-e) showed stronger anti-pancreatic cancer activity than the [1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one hybrids (8a-j) against the PANC-1 cell line. Compound 9d bearing an ortho-chlorophenyl moiety emerged as the most potent anti-pancreatic cancer agent with an IC₅₀ value of 7.7 ± 0.4 µM, much superior to the standard drug Gemcitabine (IC₅₀ > 500 µM). The discovery of these [1,3,4]thiadiazolo and [1,3,4]oxadiazolo[3,2-a]pyrimidin-5-one hybrids elicits their potentials as pursuable candidates for pancreatic cancer chemotherapy.     

A novel oxazine ring closure reaction affording (Z)-((E)-2-styrylbenzo[b]furo[3,2-d][1,3]oxazin-4-ylideno)acetaldehydes and their anti-osteoclastic bone resorption activity

A novel oxazine ring formation method was established using the reaction of 2-acetyl-(E)-3-styrylcarbonylaminobenzo[b]furans (4) with Vilsmeier-Haack-Arnold reagent to afford (E and Z)-((E)-2-styrylbenzo[b]furo[3,2-d][1,3]oxazin-4-ylideno)acetaldehydes (5). (Z)-4-(8-Bromo-(E)-2-styrylbenzo[b]furo[3,2-d][1,3]oxazin-4-ylideno)but-(E)-2-enoic acid ethyl ester (6b), derived from (Z)-5a, showed significantly potent anti-osteoclastic bone resorption activity comparable to 17beta-estradiol (E2).     

Design and synthesis of spirotryprostatin-inspired diketopiperazine systems from prolyl spirooxoindolethiazolidine derivatives

Based on the spirotryprostatin-A structure, we designed, synthesized, and evaluated different series of compounds belonging to the diketopiperazine structural class as potential cell cycle modulators and cytotoxic agents. Starting from the spirooxoindolthiazolidine scaffold, amide coupling with Pro derivatives and intramolecular cyclization reactions are suitable synthetic methods to generate chemically diverse diketopiperazine system, such as hexahydropyrrolo[1,2-a][1,3]thiazolo[3,2-d]pyrazine-5,10-dione (structure I), hexahydropyrrolo[1,2-a] [1,3]thiazolo[3,4-d]pyrazine-5,10-dione (structure II) and spiroindol-2-one[3,3′]hexahydro-5,10H-pyrrolo[1,2-a][1,3]thiazolo[3,4-d]pyrazine-5,10-dione (structure III). Some of these compounds, especially those who belong to the series I and II, showed interesting cytotoxic activity.     

Synthesis of novel hetero ring fused pyridine derivatives; Their anticancer activity,CoMFA and CoMSIA studies

A series of novel furo[2,3-b]pyridine-2-carboxamide 4a–h/pyrido[3′,2′:4,5]furo[3,2-d] pyrimidin-4(3H)-one derivatives 5a–p were prepared from pyridin 2(1H) one 1 via selective O-alkylation with α-bromoethylester followed by cyclization, then reaction with different aliphatic primary amines to obtain 4 and further reaction with triethyl orthoacetate/triethyl orthoformate. Also prepared novel furo[2,3-b]pyridine-2-carbohydrazide Schiff’s bases 7a–h and pyrido [3′,2′:4,5]furo[3,2-d]pyrimidin-4(3H)-one derivatives 8a–h starting from furo[2,3-b]pyridine carboxylate derivatives 3 by reaction with hydrazine hydrate to form 6 and reaction with diverse substituted aldehydes and cyclization. Products 4a–h, 5a–p, 7a–h and 8a–h were screened against four human cancer cell lines (HeLa, COLO205, Hep G2 and MCF 7) and one normal cell line (HEK 293). Compounds 4e, 4f, 4g, 5h, 7c, 7d, 7e and 7f showed significant anticancer activity against all the cell lines at micro molar concentration and found to be non-toxic to normal cell line. Studies for HeLa, COLO205 and MCF-7 using CoMFA and CoMSIA. Models from 3D-QSAR provided a strong basis for future rational design of more active and selective HeLa, COLO205 and MCF-7 cell line inhibitors.     

Synthesis of Pyrrolo[2′,3′:4,5]Furo[3,2-c]Pyridine-2-Carboxylic Acids

1H-Pyrrolo[2′,3′:4,5]furo[3,2-c]pyridine-2-carboxylic acid (6a) and its 1-methyl (6b) and 1-benzyl (6c) derivatives were synthesized. 3-(5-Methoxycarbonyl-4H-furo[3,2-b]-pyrrole-2-yl)propenoic acid (1) was converted to the corresponding azide 2, which in turn was cyclized to give 3 by heating in diphenylether. The pyridone 3 obtained was aromatized with phosphorus oxychloride, then reduced with zinc in acetic acid to give methyl 1H-pyrrolo[2′,3′:4,5]furo[3,2-c]pyridine-2-carboxylate (5), which by hydrolysis gave the corresponding carboxylic acid 6a.     

Practical and efficient synthesis of pyrano[3,2-c]pyridone,pyrano[4,3-b]pyran and their hybrids with nucleoside as potential antiviral and antileishmanial agents

A highly practical and efficient preparation of pyrano[3,2-c]pyridone and pyrano[4,3-b]pyran derivatives was developed via an ionic liquid mediated and promoted multi-component reaction of aldehyde (1), 4-hydroxy-pyridin-2(1H)-one or 4-hydroxy-2-pyranone (2), and malononitrile (3). As an application, a series of pyrimidine nucleoside-pyrano[3,2-c]pyridone or pyrano[4,3-b]pyran hybrids were efficiently obtained. These hybrid compounds were evaluated as potential antiviral and antileishmanial agents and showed encouraging biological activities.     

Design,synthesis, and evaluation of novel VEGFR2 kinase inhibitors: Discovery of [1,2,4]triazolo[1,5-a]pyridine derivatives with slow dissociation kinetics

For the purpose of discovering novel type-II inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2) kinase, we designed and synthesized 5,6-fused heterocyclic compounds bearing a anilide group. A co-crystal structure analysis of imidazo[1,2-b]pyridazine derivative 2 with VEGFR2 revealed that the N1-nitrogen of imidazo[1,2-b]pyridazine core interacts with the backbone NH group of Cys919. To retain this essential interaction, we designed a series of imidazo[1,2-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, thiazolo[5,4-b]pyridine, and 1,3-benzothiazole derivatives maintaining a ring nitrogen as hydrogen bond acceptor (HBA) at the corresponding position. All compounds thus designed displayed strong inhibitory activity against VEGFR2 kinase, and the [1,2,4]triazolo[1,5-a]pyridine 13d displayed favorable physicochemical properties. Furthermore, 13d inhibited VEGFR2 kinase with slow dissociation kinetics and also inhibited platelet-derived growth factor receptor (PDGFR) kinases. Oral administration of 13d showed potent anti-tumor efficacy in DU145 and A549 xenograft models in nude mice.     

A microwave-assisted facile regioselective Fischer indole synthesis and antitubercular evaluation of novel 2-aryl-3,4-dihydro-2H-thieno[3,2-b]indoles

A series of novel 2-aryl-3,4-dihydro-2H-thieno[3,2-b]indoles has been synthesised regioselectively in good yields from the reaction of 5-aryldihydro-3(2H)-thiophenones and arylhydrazine hydrochloride. This reaction is found to be assisted by microwaves. The thieno[3,2-b]indoles were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant M. tuberculosis (MDR-TB). Among 22 compounds screened, [2-(2,4-dichlorophenyl)-7-fluoro-3,4-dihydro-2H-thieno[3,2-b]indole] (6t) was found to the most active compound with MIC of 0.4 μg/mL against MTB and MDR-TB.     

Design,synthesis, and evaluation of imidazo[1,2-b]pyridazine derivatives having a benzamide unit as novel VEGFR2 kinase inhibitors

The vascular endothelial growth factor (VEGF) signaling pathway has been implicated in tumor angiogenesis, and inhibition of the VEGF pathway is considered an efficacious method for treating cancer. Herein, we describe synthetic studies of imidazo[1,2-b]pyridazine derivatives as VEGF receptor 2 (VEGFR2) kinase inhibitors. The imidazo[1,2-b]pyridazine scaffold was designed and synthesized as a hinge binder according to the previously reported crystal structure of pyrrolo[3,2-d]pyrimidine 1 with VEGFR2. Structure–activity relationship studies revealed that meta-substituted 6-phenoxy-imidazo[1,2-b]pyridazine derivatives had potent affinity for VEGFR2. In particular, N-[3-(imidazo[1,2-b]pyridazin-6-yloxy)phenyl]-3-(trifluoromethyl)benzamide (6b) exhibited strong inhibitory activity against VEGFR2 with an IC₅₀ value of 7.1 nM, and it inhibited platelet-derived growth factor receptor β kinase with an IC₅₀ value of 15 nM.     

Synthesis and SAR of thieno[3,2-b]pyridinyl urea derivatives as urotensin-II receptor antagonists

The preparation and SAR profile of thieno[3,2-b]pyridinyl urea derivatives as novel and potent urotensin-II receptor antagonists are described. An activity optimization study, probing the effects of substituents on thieno[3,2-b]pyridinyl core and benzyl group of the piperidinyl moiety, led to the identification of p-fluorobenzyl substituted thieno[3,2-b]pyridinyl urea 6n as a highly potent UT antagonist with an IC₅₀ value of 13 nM. Although 6n displays good metabolic stability and low hERG binding activity, it has an unacceptable oral bioavailability.     

Synthesis and cytotoxicity of thieno[2,3-b]quinoline-2-carboxamide and cycloalkyl[b]thieno[3,2-e]pyridine-2-carboxamide derivatives

Seventy nine derivatives of thieno[2,3-b]quinolines, tetrahydrothieno[2,3-b]quinoline, dihydrocyclopenta[b]thieno[3,2-e]pyridine, cyclohepta[b]thieno[3,2-e]pyridine and hexahydrocycloocta[b]thieno[3,2-e]pyridine were either synthesized or obtained commercially and tested for their antiproliferative activity against HCT116, MDA-MB-468 and MDA-MB-231 human cancer cell lines. The most potent eight compounds were active against all cell lines with IC₅₀ values in the 80–250 nM range. In general hexahydrocycloocta[b]thieno[3,2-e]pyridines were most active with increasing activity observed as larger cycloalkyl rings were fused to the pyridine ring.     

Facile anaerobic oxidative dehydrogenation promoted by bases: The case of copper-2,4-dihydro-1H-benzo[d][1,3]oxazine complexes

Two new 2,4-dihydro-1H-benzo[d][1,3]oxazines (L₁ and L₂) were prepared by condensation of 2-quinolinecarboxaldehyde and 2-amino-benzyl alcohols and tested as N,N’-bidentate ligands toward CuCl₂. Treatment of the resulting copper(II) derivatives with Et₃N promoted an oxidative dehydrogenation yielding the corresponding copper(I) [Cu(L-ox)Cl] complexes, 2, (L-ox = 4H-benzo[d][1,3]oxazine). The [Cu(L₂-ox)Cl] species, 2b, was characterized by single crystal X-ray diffraction, showing a trigonal geometry at the metal center and reacted with PPh₃ and CO, affording [Cu(L₂-ox)(PPh₃)Cl], 4b, and [Cu(L₂-ox)(CO)Cl], 6b, respectively. The latter species, stable in the solid state, was structurally characterized by diffraction methods and showed tetrahedral coordination of the Cu(I) ion.     

Molecular design,synthesis and docking study of benz[b]oxepines and 12-oxobenzo[c]phenanthridinones as topoisomerase 1 inhibitors

Benz[b]oxepines 4a–g and 12-oxobenzo[c]phenanthridines 5a–d were designed and synthesized as constrained forms of 3-arylisoquinolines through an intramolecular radical cyclization reaction. Radical cyclization of O-vinyl compounds preferentially led to the 7-endo-trig cyclization pathway to the benz[b]oxepines and 12-oxobenzo[c]phenanthridines through 6-exo-trig path as minor products. Among the synthesized compounds, benz[b]oxepine derivative 4e exhibited potent in vitro cytotoxicity against three different tumor cell lines, as well as topoisomerase 1 inhibitory activity. A Surflex–Dock docking study was performed to clarify the topoisomerase 1 activity of 4e.     

New benzothieno[3,2-d]-1,2,3-triazines with antiproliferative activity: Synthesis,spectroscopic studies,and biological activity

New benzothieno[3,2-d]-1,2,3-triazines, together with precursors triazenylbenzo[b]thiophenes, were designed, synthesized and screened as anticancer agents. The structural features of these compounds prompted us to investigate their DNA binding capability through UV–vis absorption titrations, circular dichroism, and viscometry, pointing out the occurrence of groove-binding. The derivative 3-(4-methoxy-phenyl)benzothieno[3,2-d]-1,2,3-triazin-4(3H)-one showed the highest antiproliferative effect against HeLa cells and was also tested in cell cycle perturbation experiments. The obtained results assessed for the first time the anticancer activity of benzothieno[3,2-d]-1,2,3-triazine nucleus, and we related it to its DNA-binding properties.     

Synthesis and antiproliferative activity of pyrrolo[3,2-b]pyridine derivatives against melanoma

Synthesis of a new series of diarylureas and amides having pyrrolo[3,2-b]pyridine scaffold is described. Their in vitro antiproliferative activity against human melanoma cell line A375 and HS 27 human fibroblast cell line was tested and the effect of substituents on the pyrrolo[3,2-b]pyridine was investigated. The newly synthesized compounds, except meta-substituted derivatives (Ij–k and Iv–w), generally showed superior or similar activity against A375 to Sorafenib. Among all of these derivatives, compounds Ir and It having 5-benzylamide substituted 4′-amide moieties showed the most potent antiproliferative activity against A375.     

Synthesis and anticonvulsant activity of some new pyrazolo[3,4-b]pyrazines and related heterocycles

A series of new pyrazolo[3,4-b]pyrazines containing, 1,2,4-oxadiazolyl, thiadiazolyl, imidazothiadiazolyl, thiazolidinonyl, substituents and other different substituents, was synthesized using 1,6-diphenyl-3-methyl-lH-pyrazolo[3,4-b]pyrazine-5-carbonitrile (2) as a starting material. Some of the newly prepared compounds were evaluated for their anticonvulsant activity. Compounds 9a, 13a–d and 14a at a dose of 10 mg/kg showed very significant anticonvulsant activity and increased the latency time of PTZ-induced tonic seizures. Compound 9b showed significant effect.