Fully Automated Synthesis and Evaluation of [18 F]BPAM121: Potential of an AMPA Receptor Positive Allosteric Modulator as PET Radiotracer.

Alzheimer's disease (AD) remains a significant burden on society. In the search for new AD drugs, modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are of particular interest, as loss of synaptic AMPARs has been linked to AD learning and memory deficits. Previously reported fluorine-containing BPAM121, an AMPA positive allosteric modulator (pam) with high activity, low toxicity, and slow metabolism, was considered to be a perfect 18 F-labeled candidate for positron emission tomography (PET) AD diagnostic investigations. For the preclinical use of this compound, an automated synthesis avoiding human radiation exposure was developed. The detailed production of [18 F]BPAM121 in relatively high quantity using a commercial FASTlab synthesizer from GE Healthcare coupled with a full set of quality controls is presented, along with procedures for the synthesis of the tosylated precursor and the fluorinated reference. To evaluate the clinical usefulness of [18 F]BPAM121 as a potential AD diagnostic, some in vivo studies in mice were then realized, alongside blocking and competition studies.

Synthesis, crystal structure and biological evaluation of some novel 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines.

Nitrogen-containing heterocycles are of particular interest and significant importance for the discovery of potent bioactive agents in pharmaceutical industry. The present study reports the synthesis of a library of new conjugated heterocycles including 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazoles (4a-g and 5a-e) and 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazines (6a-h), by cyclocondensation reaction of 4-amino-5-(pyridin-4-yl)-4H-1,2,4-triazole-3-thiol 3 with various substituted aromatic acids and phenacyl bromides, respectively. The structures of newly synthesized compounds were characterized by elemental analysis, IR, (1)H and (13)C NMR spectroscopy and in case of 4c by X-ray crystallographic analysis. Newly synthesized triazolothiadiazoles and thiadiazines were screened for acetyl- and butyryl-cholinesterases and alkaline phosphatase inhibition. Almost all of the compounds showed good to excellent activities against acetylcholinesterase more than the reference drugs. Compound 5d exhibited IC50 value 0.77 ± 0.08 µM against acetylcholinesterase and 4a showed IC50 9.57 ± 1.42 µM against butyrylcholinesterase. Among all the tested compounds, 4a also proved as excellent inhibitor of alkaline phosphatase with IC50 0.92 ± 0.03 µM. These heteroaromatic hybrid structures were also tested for their anticancer activity against lung carcinoma (H157) and kidney fibroblast (BHK-21) cell lines and leishmanias. Variable cell growth inhibitory activities were obtained and many compounds exhibit potent %inhibition.

Design, synthesis and evaluation of 3-(2-aminoheterocycle)-4-benzyloxyphenylbenzamide derivatives as BACE-1 inhibitors.

Three series of 3-(2-aminoheterocycle)-4-benzyloxyphenylbenzamide derivatives, 2-aminooxazoles, 2-aminothiazoles, and 2-amino-6H-1,3,4-thiadizines were designed, synthesized and evaluated as ß-secretase (BACE-1) inhibitors. Preliminary structure-activity relationships revealed that the existence of a 2-amino-6H-1,3,4-thiadizine moiety and α-naphthyl group were favorable for BACE-1 inhibition. Among the synthesized compounds, 5e exhibited the most potent BACE-1 inhibitory activity, with an IC50 value of 9.9 µΜ and it exhibited high brain uptake potential in Madin-Darby anine kidney cell lines (MDCK) and a Madin-Darby canine kidney-multidrug resistance 1 (MDCK-MDR1) model.

Synthesis of 3-((2,4-dichlorophenoxy)methyl)-1,2,4-triazolo(thiadiazoles and thiadiazines) as anti-inflammatory and molluscicidal agents.

A series of fused and non fused 1,2,4-triazoles with (2,4-dichlorophenoxy) moiety are prepared utilizing 3-((2,4-dichlorophenoxy)methyl)-4-amino-4H-1,2,4-triazole-5-thiol (3). The latter on reaction with carboxylic acids, ethylchloroformate, ethylcyanoacetate and sodium nitrite gives five membered fused triazole derivatives 4a-d, 5, 6, 7 and 10, respectively. The six membered heterocycles 11, 12 and 14 are prepared by cyclization of compound 3 with phenacyl bromide, chloroacetic acid and alpha-bromoketone respectively. Most of the newly synthesized compounds were screened for their anti-inflammatory and molluscicidal activities. The compounds 4b, 4d, 11 and 14 showed potent anti-inflammatory activities in dose dependent manner while compounds 3, 4b, 8 and 10 exhibited promising molluscicidal activities.

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.

Synthesis and anthelmintic activity of 3,6-disubstituted-7H-s-triazolo(3,4-b)(1,3,4)thiadiazines.

A series of 3,6-disubstituted-7H-s-triazolo(3,4-b)(1,3,4)thiadiazines was synthesized by the condensation of the appropriate 3-substituted-4-amino-5-mercapto (1,2,4) triazoles with substituted phenacyl bromides in alcoholic medium. These compounds have been studied for their in vivo anthelmintic activity in albino mice. A number of compounds showed promising activity when given by the oral route.

Studies on nitrophenylfuran derivatives part Xii. synthesis, characterization, antibacterial and antiviral activities of some nitrophenylfurfurylidene-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines.

Synthesis of four 1-aryl-3-[5-(p-nitrophenyl)-2-furyl]-2-propen-1-ones starting from substituted acetophenones and p-nitrophenylfurfuraldehyde is described. These propenones were then converted into corresponding dibromo derivatives which on dehydrobromination afforded alpha-bromopropenones rather than acetylenic ketones. Condensation of these dibromopropanones with 4-amino-5-mercapto-1,2,4-triazoles yielded a new class of nitrophenylfurfurylidene-1,2,4-triazolothiadiazines. The structures of nitrophenylfurfurylidene-1,2,4-triazolothiadiazines were established on the basis of analytical, IR, NMR and mass spectral studies. The formation of 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines rather than 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazepines in the above condensation was unambiguously confirmed by X-ray crystallographic analysis of one of them. A possible mechanism is proposed to account for the formation of nitrophenylfurfurylidene-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines. Some of the newly synthesized triazolothiadiazines were screened for their antibacterial and antiviral properties.

Benzyl derivatives of 2,1,3-benzo- and benzothieno[3,2-a]thiadiazine 2,2-dioxides: first phosphodiesterase 7 inhibitors.

The synthesis of a new family of benzyl derivatives of 2,1,3-benzo- and benzothieno[3,2-a]thiadiazine 2,2-dioxides was achieved. The biological data revealed the first heterocyclic family of compounds with PDE 7 inhibitory properties appearing to be a new objective for the treatment of T-cell-dependent disorders. The IC(50) values or percent inhibition values of the compounds against PDE 7 were calculated by testing them against human recombinant PDE 7 expressed in S. cerevisiae. In this expression system the only cyclic nucleotide hydrolyzing activity present in cell extracts corresponded to human PDE 7. Isoenzyme selectivity PDE 7 versus PDE 4 and PDE 3 was also measured. Considering simultaneously inhibition of the three different isoenzymes, monobenzyl derivatives 15 and 23 showed interesting PDE 7 potency (around 10 microM); although not statistically significant, a trend toward selectivity with respect to PDE 3 and PDE 4 was obtained. Benzothiadiazine 16, although less potent at PDE 7 (IC(50) = 25 microM), also showed a trend of selectivity toward PDE 3 and PDE 4. These compounds are considered the best leads for further optimization.

[The technology for manufacturing antiparasitic preparations. 9. The new preparation tizanox and an evaluation of its anti-Hymenolepis activity]. / Tekhnologiia proizvodstva protivoparazitarnykh preparatov. 9. Novyi preparat tizanoks i otsenka ego protivogimenolepidoznoi aktivnosti.

The paper describes a procedure for manufacturing the new anthelminthic Tizanox. It shows it necessary to administer a larger dose of the drug than that of azinox (praziquantel) to treat experimental hymenolepiasis. However, the lower toxicity of Tizanox enhances its chemotherapeutical index.

Synthesis and anti-HIV activity of 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazines (TTDs): a new family of HIV-1 specific non-nucleoside reverse transcriptase inhibitors.

The anti-HIV activity of a novel series of 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazines (TTDs) has been described. The compounds were synthesized via Curtius rearrangement of appropriate sulfamoylcarboxy azides which, in turn, were prepared from known starting materials. Several 4-substituted-2-benzyl-derivatives were found to selectively inhibit human immunodeficiency virus type 1 [HIV-1 (IIIB)] replication in MT-4 and CEM cells. These TTDs were also effective against other strains of HIV-1 (RF, HE, MN, NDK), including those that are resistant to AZT, but not against HIV-2 (ROD) or simian immunodeficiency virus [SIV(MAC251)] at subtoxic concentrations. Some of the test compounds exhibited antiviral activity against L100I RT mutant virus, but significantly lost antiviral activity against K103N, V106A, E138K, Y181C and Y188H RT mutant viruses. Compounds 6d, 6f and 6g were inhibitory to HIV-1 RT at concentrations that rank between 16.4 and 59.8 microM (nevirapine: IC50 = 4.5 microM against HIV-1 RT). Inhibition of HIV-1 RT by compound 6g was purely non-competitive with respect to the natural substrate (dGTP), which is in agreement with the nature of inhibition shown by other NNRTIs such as nevirapine and delarvidine. A structure-activity relationship was established for the anti-HIV activity of these heterocyclic compounds. TTDs represent a new chemical class of non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs).

Formation of thiazoles, thiazines, and thiadiazines from 1-phthalazine thiosemicarbazides as potential anticonvulsants.

3-Substituted-4-oxothiazolin-2-yl-(1-phthalazinyl)hydrazones, 3-substituted-4-oxo-5,6-dihydro-1,3-thiazin-2-yl-(1-phthalazinyl)hydrazones, and 2-substituted-amino-5-oxo-4-(1-phthalazinyl)-6-hydro-1,3,4-thiadiazines were prepared and tested for their anticonvulsant activity. Some compounds showed weak to moderate anticonvulsant activity.