Thieno[2,3‐d]pyrimidines in the Synthesis of Antitumor and Antioxidant Agents

Dimethyl acetylenedicarboxylate, ethyl propiolate, and E‐dibenzoylethylene react with thienopyrimidines (cyclo‐pentyl, ‐hexyl, and ‐heptyl) derivatives to form thiazolo[3,2‐a]thieno‐[2,3‐d]pyrimidin‐2‐ylidene) acetates, thieno[2,3‐d]pyrimidin‐2‐ylthioacrylates, and thieno[2′,3′:4,5]pyrimido[2,1‐b][1,3]thiazin‐6‐ones, respectively. Reactions proceed via cyclization and thio‐addition processes. Some derivatives of thienopyrimidines showed high inhibition of Hep‐G2 cell growth compared with the growth of untreated control cells. However, the fused heptyl of thienopyrimidothiazines indicates a promising specific antitumor agent against Hep‐G2 cells with IC₅₀ < 20 μM.     

Synthesis of [3H]‐labelled 4‐[Ethyl[2,5,6‐trimethyl‐7‐(2,4,6‐trimethylphenyl)pyrrolo[2,3‐d]pyrimidin‐4‐yl]amino]‐2,3‐[3H]‐butan‐1‐ol: a high affinity radioligand for the corticotropin‐releasing hormone type 1 receptor

[³H]‐Labelled 4‐[ethyl[2,5,6‐trimethyl‐7‐(2,4,6‐trimethylphenyl)pyrrolo[2,3‐d]pyrimidin‐4‐yl]amino]‐2,3‐[³H]‐butan‐1‐ol ( 3b ) was prepared as a novel non‐peptidic radiolabelled high affinity antagonist of the corticotropin‐releasing hormone type 1 receptor (CRHR₁) that could be useful as a more stable and receptor‐selective alternative to the radiolabelled peptides now used to label the CRHR₁ receptor for displacement studies in cell‐based binding assays. The precursor (Z)‐4‐[ethyl[2,5,6‐trimethyl‐7‐(2,4,6‐trimethylphenyl)pyrrolo[2,3‐d]pyrimidin‐4‐yl]amino]but‐2‐en‐1‐ol ( 2 ) was reduced with tritium gas using palladium as the catalyst. After HPLC purification 3b was obtained with a specific activity of 35 Ci/mmol in high radiochemical purity (>97%). Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis and pharmacological evaluation of 3‐(4‐chloro phenyl)‐2‐substituted‐3H‐quinazolin‐4‐ones as analgesic and anti‐inflammatory agents

A new series of 3‐(4‐chloro phenyl)‐2‐substituted‐3H‐quinazolin‐4‐ones were synthesized by reacting the amino group of 2‐hydrazino‐3‐(4‐chloro phenyl)‐3H‐quinazolin‐4‐one with different aldehydes and ketones. The compounds were investigated for their analgesic activity in albino mice, and for their anti‐inflammatory and ulcerogenic activities in Wistar rats. All test compounds exhibited analgesic and anti‐inflammatory activities. Compound VA2 (2‐(1‐ethylpropylidene‐hydrazino)‐3‐(4‐chloro phenyl)‐3H‐quinazolin‐4‐one) showed moderately more potent analgesic activity and compound VA3 (2‐(1‐methylbutylidene‐hydrazino)‐3‐(4‐chlorophenyl)‐3H‐quinazolin‐4‐one) showed moderately more potent anti‐inflammatory activity when compared with the reference standard, diclofenac sodium. The test compounds showed only mild ulcerogenic side effects when compared with aspirin. Drug Dev Res 69: 226–233, 2008 ©2008 Wiley‐Liss, Inc.     

3‐(3‐Ethylphenyl)‐2‐substituted hydrazino‐3H‐quinazolin‐4‐one Derivatives: New Class of Analgesic and Anti‐Inflammatory Agents

A new series of 3‐(3‐ethylphenyl)‐2‐substituted hydrazino‐3H‐quinazolin‐4‐ones were synthesized by reacting the amino group of 2‐hydrazino‐3‐(3‐ethylphenyl)‐3H‐quinazolin‐4‐one with a variety of aldehydes and ketones. The title compounds were investigated for analgesic, anti‐inflammatory and ulcerogenic index behavior. The compound 2‐(N′‐3‐pentylidene‐hydrazino)‐3‐(3‐ethylphenyl)‐3H‐quinazolin‐4‐one ( AS2 ) emerged as the most active compound in exhibiting analgesic activity and the compound 2‐(N′‐2‐pentylidene‐hydrazino)‐3‐(3‐ethylphenyl)‐3H‐quinazolin‐4‐one ( AS3 ) emerged as the most active compound in exhibiting anti‐inflammatory activity; and these compounds are moderately potent when compared with the reference standard diclofenac sodium. Interestingly, the test compounds showed only mild ulcerogenic potential when compared with aspirin.     

Pyrazolo[3,4‐d]pyrimidine Derivatives as COX‐2 Selective Inhibitors: Synthesis and Molecular Modelling Studies

The pyrazolo[3,4‐d]pyrimidine system shows a multitude of interesting pharmacological properties. Owing to the potential anti‐inflammatory activity of 5‐benzamido‐pyrazolo[3,4‐d]pyrimidin‐4‐one derivatives and considering the easy synthesis of this class of compounds, a set of new 5‐benzamido‐1H‐pyrazolo[3,4‐d]pyrimidin‐4‐ones has been prepared in 42‐80% yields by reacting 5‐aminopyrazole‐4(N‐benzoyl)carbohydrazide derivatives and the opportune triethylorthoesters. Compounds 8a , b , 10a – d , and 11a , b revealed a superior inhibitory profile against COX‐2, when compared to that of reference standards NS398 and indomethacin. Molecular modelling studies confirmed the obtained biological results.     

Synthesis of doubly 13C‐labelled antalarmin isotopomers for pharmacokinetic studies

Antalarmin (butyl‐ethyl‐[2,5,6‐trimethyl‐7‐(2,4,6‐trimethyl‐phenyl)‐7H‐pyrrolo[2,3‐d]pyrimidin‐4‐yl]‐amine) was doubly labelled with carbon‐13. The synthesized butyl‐[¹³C₂]ethyl‐[2,5,6‐trimethyl‐7‐(2,4,6‐trimethyl‐phenyl)‐7H‐pyrrolo[2,3‐d]pyrimidin‐4‐yl]‐amine ( 1 ) and butyl‐ethyl‐[2‐¹³C]‐[2,5,6‐trimethyl‐7‐(2,4,6‐trimethyl‐phenyl)‐7H‐pyrrolo[2,3‐d]‐[2‐¹³C] pyrimidin‐4‐yl]‐amine, ( 2 ) were prepared for use as substrates for pharmacokinetic studies. These compounds were obtained in fair overall yield in a 5 and 6 step synthesis (20–24.5%, respectively) and high isotopic purity (about 99 at% ¹³C). Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of 5,6‐dihydro‐4H‐benzo[d]isoxazol‐7‐one and 5,6‐dihydro‐4H‐isoxazolo[5,4‐c]pyridin‐7‐one Derivatives as Potential Hsp90 Inhibitors

A novel class of 5,6‐dihydro‐4H‐benzo[d]isoxazol‐7‐ones and 5,6‐dihydro‐4H‐isoxazolo[5,4‐c]pyridin‐7‐ones was designed, synthesized, and assayed to investigate the affinity toward Hsp90 protein. The synthetic route was based on a 1,3‐dipolar cycloaddition of nitriloxides, generated in situ from suitable benzaldoximes, with 2‐bromocyclohex‐2‐enones or 3‐bromo‐5,6‐dihydro‐1H‐pyridin‐2‐ones. Whereas all the compounds bearing a benzamide group on the bicyclic scaffold were devoid of activity, the derivatives carrying a resorcinol‐like fragment showed a remarkable inhibitory effect on Hsp90. Docking calculations were performed to investigate the orientation of the new compounds within the binding site of the enzyme.     

Novel Thiophenes,Thienopyrimidines, and Triazolothienopyrimidines for the Evaluation of Anticancer and Augmentation Effects of γ‐Radiation

New derivatives of thiophenes 2 , 12 , iminoaminothieno[2,3‐d]pyrimidines 3 , 5 , and 6 , triazolothieno[2,3‐d]pyrimidines 8–11 , pyrazolo‐ and triazinothieno[2,3‐d]pyrimidines 4 , 7 , respectively, have been prepared by different synthetic procedures. Structure elucidation of the newly synthesized compounds was carried out via elemental analyses and spectral data. The antitumor activity of compounds 2 , 3 , and 9–12 was evaluated against in‐vitro cell lines (HEPG‐2 and MCF‐7). Compounds 2 , 3 , 10 , 11 , and 12 showed significant in‐vitro cytotoxic activity against hepatocellular carcinoma (HEPG‐2) compared to the reference drug Doxorubicin. Compound 2 showed significant in‐vitro cytotoxic activity against breast cancer (MCF‐7) cells compared to the reference drug Doxorubicin. The augmenting effect of γ‐radiation was assessed; here, compounds 2 , 3 , 10 , and 11 showed the most potent in‐vitro anticancer activity.     

Synthesis of isotope‐labeled HSP90 inhibitor: [13CD3] and [14C]‐TAK‐459

[¹³CD₃]‐TAK‐459 (1A), an HSP90 inhibitor, was synthesized from [¹³CD₃]‐sodium methoxide in three steps in an overall yield of 29%. The key intermediate [¹³CD₃]‐2‐methoxy‐6‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)pyridine was synthesized in two steps from 2,6‐dibromopyridine and stable isotope‐labeled sodium methoxide. [¹⁴C]‐TAK‐459 (1B) was synthesized from [¹⁴C(U)]‐guanidine hydrochloride in five steps in an overall radiochemical yield of 5.4%. The key intermediate, [¹⁴C]‐(R)‐2‐amino‐7‐(2‐bromo‐4‐fluorophenyl)‐4‐methyl‐7,8‐dihydropyrido[4,3‐d]pyrimidin‐5(6H)‐one, was prepared by microwave‐assisted condensation.     

Synthesis of New 2,3‐Dihydroquinazolin‐4(1H)‐one Derivatives for Analgesic and Anti‐inflammatory Evaluation

Starting from isatoic anhydrides, several new 2,3‐dihydroquinazolin‐4(1H)‐one derivatives bearing chalcone or pyrazole or thiazole moieties at the third position were synthesized. The analgesic and anti‐inflammatory activities for most compounds were studied at a dose level of 50 mg/kg via the acetic‐acid‐induced writhing‐response method and carrageenan‐induced edema method, respectively. The study showed that the chalcones bearing a 4‐chlorophenyl group 4c or 4‐nitrophenyl group 4b were the most active ones as analgesics. Both chalcone 4c and N‐phenyl pyrazole bearing 4‐methoxy phenyl group 5b showed a higher anti‐inflammatory activity than celecoxib but still lower than that of diclofenac sodium. Moreover, the chalcone 4c has nearly the same ulcerogenic index as the selective cyclooxygenase‐2 inhibitor celecoxib.     

Synthesis and mycobacterial evaluation of 5‐substituted‐6‐acetyl‐2‐amino‐7‐methyl‐5,8‐dihydropyrido‐[2,3‐d]pyrimidin‐4(3H)‐one derivatives

5‐Substituted‐6‐acetyl‐2‐amino‐7‐methyl‐5,8‐dihydropyrido[2,3‐d]pyrimidin‐4(3H)‐one derivatives were synthesized and evaluated against Mycobacterium tuberculosis H37Rv, Mycobacterium aurum, Escherichia coli, and Staphylococcus aureus as well as a human monocyte‐derived macrophage (THP‐1), and murine macrophage (RAW 264.7) cell lines to assess their antibacterial and cytotoxic potential, respectively. The compounds showed activity in the range of 1.95–125 µg/ml against M. tuberculosis but showed no activity against M. aurum, E. coli, and S. aureus, indicating selectivity towards slow‐growing mycobacterial pathogens. The compounds exhibited very low to no cytotoxicity up to 500 µg/ml concentration against eukaryotic cell lines. The most potent molecule, 2l , showed a minimum inhibitory concentration of 1.95 µg/ml against M. tuberculosis H37Rv and a selectivity index of >250 against both the eukaryotic cell lines. Furthermore, 2l showed moderate inhibition of whole‐cell mycobacterial drug‐efflux pumps when compared to verapamil, a known potent inhibitor of efflux pumps. Thus, derivative 2l was identified as an antituberculosis hit molecule, which could be used to yield more potent lead molecules.     

Mehrcyclische Azine mit Heteroatomen in 1- und 3-Stellung, 40. Mitt. Synthese heterocyclischer Immunmodulatoren, 2. Mitt.: 3-Mercaptoalkylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione: Synthese und Prüfung auf immunstimulatorische Wirksamkeit

Polycyclic Azines, XL: Synthesis of Heterocyclic Immunomodulators, II: 3-Mercaptoalkylthieno[2,3-d]pyrimidine-2,4(1H,3H)-diones: Synthesis and Test for Immuno-stimulating Activity A series of 3-mercaptoalkylthieno[2,3-d]pyrimidine-2,4(1H,3H)-diones 3 was prepared and their immuno-stimulating activity was examined. The title compounds were obtained conveniently by hydrolytic ring cleavage of fused thiazolo- or 1,3-thiazino-thicnopyrimidines 1 under alkaline or acidic reaction conditions. The ms fragmentation of the thieno[2,3-d]pyrimidine-2,4-diones 3 is discussed. In the delayed type hypersensitivity (DTH) test some compounds 3 showed immuno-stimulating activities in the range of isoprinosine.     

Synthesis,p38α MAP kinase inhibition,anti‐inflammatory activity,and molecular docking studies of 1,2,4‐triazole‐based benzothiazole‐2‐amines

Recent studies have demonstrated that inhibition of p38α MAP kinase could effectively inhibit pro‐inflammatory cytokines including TNF‐α and interleukins. Thus, inhibition of this enzyme can prove greatly beneficial in the therapy of chronic inflammatory diseases. A new series of N‐[3‐(substituted‐4H‐1,2,4‐triazol‐4‐yl)]‐benzo[d]thiazol‐2‐amines ( 4a–n ) were synthesized and subjected to in vitro evaluation for anti‐inflammatory activity (BSA anti‐denaturation assay) and p38α MAPK inhibition. Among the compounds selected for in vivo screening of anti‐inflammatory activity ( 4b , 4c , 4f , 4g , 4j , 4m , and 4n ), compound 4f was found to be the most active with an in vivo anti‐inflammatory efficacy of 85.31% when compared to diclofenac sodium (83.68%). It was also found to have a low ulcerogenic risk and a protective effect on lipid peroxidation. The p38α MAP kinase inhibition of this compound (IC₅₀ = 0.036 ± 0.12 μM) was also found to be superior to the standard SB203580 (IC₅₀ = 0.043 ± 0.27 μM). Furthermore, the in silico binding mode of the compound on docking against p38α MAP kinase exemplified stronger interactions than those of SB203580.

     

Synthesis of deuterium‐labeled 3‐O‐methyldopa and 4‐O‐methyldopa

Concise methods for the synthesis of 4‐hydroxy‐3‐[²H₃]‐methoxyphenylalanine (3‐O‐[²H₃]‐methydopa) and 3‐hydroxy‐4‐[²H₃]‐methoxyphenylalanine (4‐O‐[²H₃]‐methydopa) are described. The 3‐O‐[²H₃]‐methydopa is a valuable internal standard for the tandem MS quantification of 3‐O‐methyldopa, a metabolite of value in the diagnosis of aromatic l‐amino acid decarboxylase (AADC) deficiency. Copyright © 2003 John Wiley & Sons, Ltd.     

1,3-Bis(pyridin-2-ylthio)propan-2-one,Bis(thieno[2,3-b]pyridin-2-yl)-ketone und 5H-Bispyrido[3′,2′:4,5]thieno[2,3-b:2′,3′-e]pyridin-11-one

1,3-Bis(pyridin-2-ylthio)propan-2-ones, Bis(thieno[2,3-b]pyridin-2-yl)ketones and 5H-Bispyrido[3′,2′:4,5]thieno[2,3-b:2′,3′-e]pyridin-11-ones Reaction of 1a-d with 1,3-dichloroacetone gives the bissulphides 2a-d . Base catalyzed cyclization of 2a-d affords heterocyclically substituted ketones 3a-e . Treatment of 3a and 3b in conc. H₃PO₄ leads to the bispyridothienopyridines 5a and 5b .     

Synthesis of a deuterium‐labelled standard of bufotenine (5‐HO‐DMT)

The Batcho–Leimgruber strategy was employed to synthesize 3‐(2‐dimethylamino‐[²H₄]‐ethyl)‐1H‐indol‐5‐ol (bufotenine, 5‐HO‐DMT) ( 8 ) from commercial 3‐methyl‐4‐nitro‐phenol ( 1 ), benzyl bromide and N,N–dimethylformamide–dimethylacetal. Compound 4 was synthesized from compound 3 using the Batcho–Leimgruber strategy in the presence of Raney nickel and hydrazine hydrate. Compound 4 was treated with oxalyl chloride, dimethylamine and lithium aluminum [²H₄]‐hydride to yield [2‐(5‐benzyloxy‐1H‐indol‐3‐yl)‐[²H₄]‐ethyl]‐dimethyl‐amine ( 7 ). The benzyl ether in compound 7 was cleaved by hydrogenolysis to give bufotenine 8 . Copyright © 2007 John Wiley & Sons, Ltd.     

Synthesis and Evaluation of Novel 2‐Substituted‐quinazolin‐4(3H)‐ones as Potent Analgesic and Anti‐inflammatory Agents

A novel series of 2‐substituted‐quinazolin‐4(3H)‐ones were synthesized by reacting 3,5‐disubstituted‐anthranilic acid with acetic anhydride/benzoyl chloride, which were further reacted with different primary amines to obtain 2,6,8‐substituted‐quinazolin‐4(3H)‐ones 6a–f , 7 , 8 . All the synthesized compounds were characterized and screened for analgesic and anti‐inflammatory activities. Compounds 6,8‐dibromo‐2‐phenyl‐3‐(4′‐carboxyl phenyl)quinazolin‐4(3H)‐one 7 and 6,8‐dibromo‐2‐phenyl‐3‐(2′‐phenylethanoic acid)quinazolin‐4(3H)‐one 8 displayed good analgesic and anti‐inflammatory activity in comparison to the reference standards acetyl salicylic acid and indomethacin, respectively.     

New pyrazole derivative 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole: synthesis and assessment of some biological activities

The molecular modification and synthesis of compounds is vital to discovering drugs with desirable pharmacological and toxicity profiles. In response to pyrazole compounds' antipyretic, analgesic, and anti‐inflammatory effects, this study sought to evaluate the analgesic, anti‐inflammatory, and vasorelaxant effects, as well as the mechanisms of action, of a new pyrazole derivative, 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole. During the acetic acid‐induced abdominal writhing test, treatments with 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole reduced abdominal writhing, while during the formalin test, 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole reduced licking times in response to both neurogenic pain and inflammatory pain, all without demonstrating any antinociceptive effects, as revealed during the tail flick test. 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole also reduced carrageenan‐induced paw edema and cell migration during the carrageenan‐induced pleurisy test. As demonstrated by the model of the isolated organ, 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole exhibits a vasorelaxant effect attenuated by Nω‐nitro‐l ‐arginine methyl ester, 1H‐[1,2,4]oxadiazolo[4,3‐alpha]quinoxalin‐1‐one, tetraethylammonium or glibenclamide. 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole also blocked CaCl₂‐induced contraction in a dose‐dependent manner. Suggesting a safe toxicity profile, 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole reduced the viability of 3T3 cells at higher concentrations and was orally tolerated, despite signs of toxicity in doses of 2000 mg/kg. Lastly, the compounds' analgesic activity might be attributed to the involvement of the NO/cGMP pathway and K⁺ channels observed in the vasorelaxant effect.     

Novel 3,6‐Disubstituted 7H‐1,2,4‐Triazolo[3,4‐b][1,3,4]thiadiazines: Synthesis,Characterization, and Evaluation of Analgesic / Anti‐inflammatory,Antioxidant Activities

In this study, the synthesis of a new series of 3,6‐disubstituted‐7H‐1,2,4‐triazolo[3,4‐b][1,3,4]thiadiazine 1a – 4c compounds derived from 4‐amino‐3‐substituted‐1,2,4‐triazole‐5‐thiones 1 – 4 is described. All of the synthesized compounds were screened for their possible analgesic / anti‐inflammatory, antioxidant activities and gastric toxicity. The compound 2c was found to have both significant analgesic and consistent anti‐inflammatory activity without inducing any gastric lesions along with minimal lipid peroxidation. A deep insight into the structures of the active compounds revealed that the compounds carrying an electron withdrawing group (a chloride or fluoride) on the phenyl ring at 6‐position of the condensed heterocyclic derivatives exhibited noticeable higher activity.     

Radiosynthesis of 3‐(2′‐[18F]fluoro)‐flumazenil ([18F]FFMZ)

Recently, two fluorine‐18 labelled derivatives of flumazenil were described: 5‐(2′‐[¹⁸F]fluoroethyl)‐5‐desmethylflumazenil (ethyl 8‐fluoro‐5‐[¹⁸F]fluoroethyl‐6‐oxo‐5,6‐dihydro‐4H‐benzo‐[f]imidazo[1,5‐a] [1,4]diazepine‐3‐carboxylate; [¹⁸F]FEFMZ) and 3‐(2′‐[¹⁸F]fluoro)‐flumazenil (2′‐[¹⁸F]fluoroethyl 8‐fluoro‐5‐methyl‐6‐oxo‐5,6‐dihydro‐4H‐benzo‐[f]imidazo[1,5‐a]‐[1,4]diazepine‐3‐carbo‐ xylate; [¹⁸F]FFMZ). Since the biodistribution data of the latter were superior to those of the former we developed a synthetic approach for [¹⁸F]FFMZ starting from a commercially available precursor, thereby obviating the need to prepare a precursor by ourselves. The following two‐step procedure was developed: First, [¹⁸F]fluoride was reacted with 2‐bromoethyl triflate using the kryptofix/acetonitrile method to yield 2‐bromo‐[¹⁸F]fluoroethane ([¹⁸F]BFE). In the second step, distilled [¹⁸F]BFE was reacted with the tetrabutylammonium salt of 3‐desethylflumazenil (8‐fluoro‐5‐methyl‐6‐oxo‐5,6‐dihydro‐4H‐benzo‐[f]imidazo[1,5‐a] [1,4]diazepine‐3‐carboxylic acid) to yield [¹⁸F]FFMZ. The synthesis of [¹⁸F]FFMZ allows for the production of up to 7 GBq of this PET‐tracer, enough to serve several patients. [¹⁸F]FFMZ synthesis was completed in less than 80 min and the radiochemical purity exceeded 98%. Copyright © 2003 John Wiley & Sons, Ltd.