- Acylated 1 H-1,2,4-Triazol-5-Amines Targeting Human Coagulation Factor XIIa and Thrombin: Conventional and Microscale Synthesis, Anticoagulant Properties, and Mechanism of Action
-
We herein report the conventional and microscale parallel synthesis of selective inhibitors of human blood coagulation factor XIIa and thrombin exhibiting a 1,2,4-Triazol-5-Amine scaffold. Structural variations of this scaffold allowed identifying derivative 21i, a potent 29 nM inhibitor of FXIIa, with improved selectivity over other tested serine proteases and also finding compound 21m with 27 nM inhibitory activity toward thrombin. For the first time, acylated 1,2,4-Triazol-5-Amines were proved to have anticoagulant properties and the ability to affect thrombin-And cancer-cell-induced platelet aggregation. Performed mass spectrometric analysis and molecular modeling allowed us to discover previously unknown interactions between the synthesized inhibitors and the active site of FXIIa, which uncovered the mechanistic details of FXIIa inhibition. Synthesized compounds represent a promising starting point for the development of novel antithrombotic drugs or chemical tools for studying the role of FXIIa and thrombin in physiological and pathological processes.
- Korff, Marvin,Imberg, Lukas,Will, Jonas M.,Bückrei?, Nico,Kalinina, Svetlana A.,Wenzel, Benjamin M.,Kastner, Gregor A.,Daniliuc, Constantin G.,Barth, Maximilian,Ovsepyan, Ruzanna A.,Butov, Kirill R.,Humpf, Hans-Ulrich,Lehr, Matthias,Panteleev, Mikhail A.,Poso, Antti,Karst, Uwe,Steinmetzer, Torsten,Bendas, Gerd,Kalinin, Dmitrii V.
-
supporting information
p. 13159 - 13186
(2020/11/13)
-
- A green one-pot synthesis of 3(5)-substituted 1,2,4-triazol-5(3)-amines as potential antimicrobial agents
-
Abstract: An efficient procedure was proposed for the synthesis of 3(5)-substituted 1,2,4-triazol-5(3)-amines via a one-pot reaction of thiourea, dimethyl sulfate and various hydrazides. 1,2,4-Triazole derivatives were prepared in aqueous media under mild conditions while adhering to some principles of green chemistry. The products were easily isolated in 83–95% yields without any need for further purification. Inhibitory activities of all synthetic compounds were assessed against a variety of Gram-positive and Gram-negative pathogenic bacteria as well as some fungal pathogens. The best antibacterial effects were observed with 3(5)-phenyl-1H-1,2,4-triazol-5(3)-amine according to its MIC values (4–8?μg?mL?1). All compounds were successful in blocking the growth of fungi. Acceptable antioxidant properties were observed only with 3(5)-(4-nitrophenyl)-1H-1,2,4-triazol-5(3)-amine. Graphic abstract: 3(5)-Substituted 1,2,4-triazol-5(3)-amines were efficiently prepared via a one-pot reaction of thiourea, dimethyl sulfate and various hydrazides in water as the solvent. Inhibitory activity of all synthesized derivatives was proved according to their MIC, MBC and MFC values. It is found that they are potential antifungal agents.[Figure not available: see fulltext.].
- Beyzaei, Hamid,Khosravi, Zahra,Aryan, Reza,Ghasemi, Behzad
-
p. 2565 - 2573
(2019/07/04)
-
- 3-Aryl/Heteroaryl-5-amino-1-(3′,4′,5′-trimethoxybenzoyl)-1,2,4-triazoles as antimicrotubule agents. Design, synthesis, antiproliferative activity and inhibition of tubulin polymerization
-
Many natural and synthetic substances are known to interfere with the dynamic assembly of tubulin, preventing the formation of microtubules. In our search for potent and selective antitumor agents, a novel series of 1-(3′,4′,5′-trimethoxybenzoyl)-5-amino-1,2,4-triazoles were synthesized. The compounds had different heterocycles, including thiophene, furan or the three isomeric pyridines, and they possessed a phenyl ring bearing electron-releasing or electron-withdrawing substituents at the 3-position of the 5-amino-1,2,4-triazole system. Most of the twenty-two tested compounds showed moderate to potent antiproliferative activities against a panel of solid tumor and leukemic cell lines, with four (5j, 5k, 5o and 5p) showing strong antiproliferative activity (IC50 50 values 2-100-fold lower for Jurkat and RS4;11 cells than those for the three lines derived from solid tumors (HeLa, HT-29 and MCF-7 cells). Compound 5k strongly inhibited tubulin assembly, with an IC50 value of 0.66 μM, half that obtained in simultaneous experiments with CA-4 (IC50 = 1.3 μM).
- Romagnoli, Romeo,Prencipe, Filippo,Oliva, Paola,Baraldi, Stefania,Baraldi, Pier Giovanni,Brancale, Andrea,Ferla, Salvatore,Hamel, Ernest,Bortolozzi, Roberta,Viola, Giampietro
-
p. 361 - 374
(2018/07/13)
-
- FUSED TRIAZOLO-PYRIMIDINE COMPOUNDS HAVING USEFUL PHARMACEUTICAL APPLICATION
-
A compound and/or a pharmaceutically acceptable salt thereof has the following formula A: These compounds can be PIKfyve kinase inhibitors.
- -
-
Paragraph 0082
(2018/10/19)
-
- Design, Synthesis, and Evaluation of the Highly Selective and Potent G-Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitor for the Potential Treatment of Heart Failure
-
A novel class of therapeutic drug candidates for heart failure, highly potent and selective GRK2 inhibitors, exhibit potentiation of β-adrenergic signaling in vitro studies. Hydrazone derivative 5 and 1,2,4-triazole derivative 24a were identified as hit compounds by HTS. New scaffold generation and SAR studies of all parts resulted in a 4-methyl-1,2,4-triazole derivative with an N-benzylcarboxamide moiety with highly potent activity toward GRK2 and selectivity over other kinases. In terms of subtype selectivity, these compounds showed enough selectivity against GRK1, 5, 6, and 7 with almost equipotent inhibition to GRK3. Our medicinal chemistry efforts led to the discovery of 115h (GRK2 IC50 = 18 nM), which was obtained the cocrystal structure with human GRK2 and an inhibitor of GRK2 that potentiates β-adrenergic receptor (βAR)-mediated cAMP accumulation and prevents internalization of βARs in β2AR-expressing HEK293 cells treated with isoproterenol. Therefore, 115h appears to be a novel class of therapeutic for heart failure treatment.
- Okawa, Tomohiro,Aramaki, Yoshio,Yamamoto, Mitsuo,Kobayashi, Toshitake,Fukumoto, Shoji,Toyoda, Yukio,Henta, Tsutomu,Hata, Akito,Ikeda, Shota,Kaneko, Manami,Hoffman, Isaac D.,Sang, Bi-Ching,Zou, Hua,Kawamoto, Tetsuji
-
p. 6942 - 6990
(2017/09/07)
-
- MULTISUBSTITUTED AROMATIC COMPOUNDS AS INHIBITORS OF THROMBIN
-
There are provided inter alia multisubstituted aromatic compounds useful for the inhibition of thrombin, which compounds include substituted pyrazolyl or substituted triazolyl. There are additionally provided pharmaceutical compositions. There are additionally provided methods of treating and preventing a disease or disorder, which disease or disorder is amenable to treatment or prevention by the inhibition of thrombin.
- -
-
Paragraph 0229-0231; 0234-0235
(2017/12/07)
-
- MULTISUBSTITUTED AROMATIC COMPOUNDS AS SERINE PROTEASE INHIBITORS
-
There are provided inter alia multisubstituted aromatic compounds useful for the inhibition of kallikrein, which compounds include substituted pyrazolyl or substituted triazolyl. There are additionally provided pharmaceutical compositions. There are additionally provided methods of treating and preventing certain diseases or disorders, which disease or disorder is amenable to treatment or prevention by the inhibition of kallikrein.
- -
-
Paragraph 0211
(2014/09/29)
-
- Synthesis of 3-pyridyl-substituted 5-amino-1,2,4-triazoles from aminoguanidine and pyridinecarboxylic acids
-
Effect of the molar ratio between reagents, temperature, and synthesis duration on the yield of 3-pyridylsubstituted 5-amino-1,2,4-triazoles in the reaction of aminoguanidine hydrochloride with pyridinecarboxylic acids under acid catalysis conditions was studied. A single-reactor method for synthesis of 3-pyridyl-substituted 5-amino-1,2,4-triazoles and their hydrochlorides was developed.
- Chernyshev,Tarasova,Chernysheva,Taranushich
-
experimental part
p. 1890 - 1896
(2012/03/12)
-
- MULTISUBSTITUTED AROMATIC COMPOUNDS AS INHIBITORS OF THROMBIN
-
There are provided inter alia multisubstituted aromatic compounds useful for the inhibition of thrombin, which compounds include substituted pyrazolyl or substituted triazolyl. There are additionally provided pharmaceutical compositions. There are additionally provided methods of treating and preventing a disease or disorder, which disease or disorder is amenable to treatment or prevention by the inhibition of thrombin.
- -
-
Page/Page column 66
(2011/10/31)
-
- Synthesis of amino-1,2,4-triazoles by reductive ANRORC rearrangements of 1,2,4-oxadiazoles
-
The reaction of various 1,2,4-oxadiazoles with an excess of hydrazine in DMF has been investigated. 3-Amino-1,2,4-triazoles are produced through a reductive ANRORC pathway consisting of the addition of hydrazine to the 1,2,4-oxadiazole followed by ring-opening, ring-closure, and final reduction of the 3-hydroxylamino-1,2,4-triazole intermediate. The general applicability of 1,2,4-oxadiazoles ANRORC reactivity is demonstrated also in the absence of C(5)-linked electron-withdrawing groups.
- Palumbo Piccionello, Antonio,Guarcello, Annalisa,Buscemi, Silvestre,Vivona, Nicolo,Pace, Andrea
-
experimental part
p. 8724 - 8727
(2011/03/19)
-
- An aqueous medium synthesis and tautomerism study of 3(5)-amino-1,2,4-triazoles
-
A catalyst-free highly efficient synthesis of 3(5)-amino-5(3)-(het)aryl-1,2,4-triazoles in aqueous medium was performed using conventional heating and microwave irradiation. The tautomerism in the products was investigated using NMR spectroscopy and X-ray crystallography. The effects of the substitution, temperature, solvents, and concentration on the tautomerism were studied. The triazoles were found to exist in 1H-forms, the 4H-form was not observed either in solid state or in solution. In general, 5-amino-1,2,4-triazoles were electronically preferred in the tautomeric equilibrium, but some exceptions from the established relationship were also identified.
- Dolzhenko, Anton V.,Pastorin, Giorgia,Dolzhenko, Anna V.,Chui, Wai Keung
-
experimental part
p. 2124 - 2128
(2009/07/26)
-
- Synthesis of 5,7-diamino1,2,4 triazolo[1,2-a1,3,5 triazines via annulation of 1,3,5-triazine ring onto 3(5)-amino-1,2,4-triazoles
-
The 5,7-diamino[1,2,4]triazoeo[1,5-a][1,3,5]triazines were synthesized by cyclocondensation of 3(5)-amino-1,2,4-triazoles with cyanoguanidine. The substituted 3(5)-amino-1,2,4-triazoles were prepared from corresponding hydrazides and S-methylisothiourea via ring closure of the intermediate acylaminoguanidines. The 3,5-diamino-1,2,4-triazoles were prepared using partial aminolysis of dimethyl N-cyanodithiocarbonimidate followed by cyclization of the obtained N-substituted N′-cyano-S-methylisothioureas with hydrazine. The structures of the prepared compound were confirmed using NMR spectral data.
- Dolzhenko, Anton V.,Dolzhenko, Anna V.,Chui, Wai-Keung
-
p. 429 - 436
(2008/02/09)
-
- Synthesis and evaluation of anti-HIV-1 and anti-HSV-1 activities of 4H-[1,2,4]-triazolo[1,5-a]pyrimidin-5-one derivatives
-
In a one pot procedure, 18 compounds of 7-(substituted phenyl)-2-substituted-6,7-dihydro-4H-[1,2,4] triazolo [1,5-a] pyrimidin-5-one derivatives (16-33) have been synthesized. 3(5)-Amino-5(3)-substituted-1,2,4-triazole derivatives (7-12) were used as synthones which were cyclocondensed by fusion with substituted methyl cinnamate esters (13-15) to afford the target compounds (16-33). In an effort to develop new non-nucleoside antiviral agents, compounds 16-33 were evaluated for their anti-HIV-1 and anti-HSV-1 activities. Complete inhibition of the proliferation of HIV-1 viruses was achieved by compounds 22, 23 and 24 at concentrations of 25, 25 and 50 μg/ml, respectively. 7-Phenyl-2-(n-pentyl)-6,7-dihydro-4H-[1,2,4]triazolo[1,5-a]pyrimidin-5-one (19) exhibited potential activity against HSV-I with 88% reduction in the viral plaques. The suggested marked specificity of this class of compounds as anti-HIV-1 and HSV-1 agents is discussed.
- Abdel-Hafez, Atef A.,Elsherief, Hosny A. H.,Jo, Michiko,Kurokawa, Masahiko,Shiraki, Kimiyasu,Kawahata, Takuya,Otake, Toru,Nakamura, Norio,Hattori, Masao
-
p. 833 - 839
(2007/10/03)
-
- Pseudosymmetry and Bioisosterism in Biaryl Pyridyl Competitive Histamine H2-Receptor Antagonists
-
A process of drug design has previously been described that led to the synthesis of 3-amino-5--1,2,4-triazole (4), a competitive histamine H2-receptor antagonist structurally unrelated to, but more potent than, cimetidine.A QSAR study on a subset of analogues closely related to 4 showed that gastric acid antisecretory activity increased with decreasing lipophilicity.An SAR study about 4 focused on (1) pyridine substitution compatible with both unidentate and bidentate hydrogen bonding, (2) exploration of the pseudosymmetry of 4, and (3) examination of triazole and imidazole bioisosterism.This SAR study led to a definition of the minimum structural features required for antagonist activity.The pyridylamino group is not essential for activity since replacement with a methyl group results in a decrease but not loss of activity.The triazole amino group is also not essential since replacement of the triazole amino group by methyl results in very similar activity.A triazole ring nitrogen N-1 can be replaced by a CH as in imidazole 20.The same methylimidazole in 20 when appended to a methyl pyridine as in 22 produces a competitive antagonist with Schild plot slope of unity.In summary compound 22 displays the minimum features required for antagonist activity, namely a 4-substituted pyridine appended to a 4(5)-substituted imidazole ring with single nitrogen to amidine nitrogen pair distances of 5.16 and 6.42 Angstroem.
- Lipinski, Christopher A.,LaMattina, John L.,Hohnke, Lyle A.
-
p. 1628 - 1636
(2007/10/02)
-
- Bioisosteric Design of Conformationally Restricted Pyridyltriazole Histamine H2-Receptor Antagonists
-
A process of bioisosteric drug design is described whereby, in a manner analogous to synthesis, key portions of an effector molecule are successively replaced by pharmacophores or bioisosteres.This process, when applied to histamine, leads to the competitive histamine H2-receptor antagonist prototype 3-amino-5-(2-amino-4-pyridyl)-1,2,4-triazole (7).The biaryl nature of 7 fixes internitrogen distances, and comparison of these with histamine suggests that 7 shares structural features more in common with histamine trans rather than histamine gauche conformations.Alkylation of the prototype pyridylamino group in 7 markedly improves both histamine H2-receptor antagonist and gastric acid antisecretory activity so that the resulting agent, 3-amino-5--1,2,4-triazole (8), is more active than cimetidine.
- Lipinski, Christopher A.
-
-