- Microscale Parallel Synthesis of Acylated Aminotriazoles Enabling the Development of Factor XIIa and Thrombin Inhibitors
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Herein we report a microscale parallel synthetic approach allowing for rapid access to libraries of N-acylated aminotriazoles and screening of their inhibitory activity against factor XIIa (FXIIa) and thrombin, which are targets for antithrombotic drugs. This approach, in combination with post-screening structure optimization, yielded a potent 7 nM inhibitor of FXIIa and a 25 nM thrombin inhibitor; both compounds showed no inhibition of the other tested serine proteases. Selected N-acylated aminotriazoles exhibited anticoagulant properties in vitro influencing the intrinsic blood coagulation pathway, but not extrinsic coagulation. Mechanistic studies of FXIIa inhibition suggested that synthesized N-acylated aminotriazoles are covalent inhibitors of FXIIa. These synthesized compounds may serve as a promising starting point for the development of novel antithrombotic drugs.
- Platte, Simon,Korff, Marvin,Imberg, Lukas,Balicioglu, Ilker,Erbacher, Catharina,Will, Jonas M.,Daniliuc, Constantin G.,Karst, Uwe,Kalinin, Dmitrii V.
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supporting information
p. 3672 - 3690
(2021/08/07)
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- Discovery of [1,2,4]-triazolo [1,5-a]pyrimidine-7(4H)-one derivatives as positive modulators of GABAA1 receptor with potent anticonvulsant activity and low toxicity
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In searching for more effective and safer antiepileptic drugs, a series of 2,5-disubstituted [1,2,4]-triazolo[1,5-a]pyrimidine-7(4H)-one derivatives were designed and synthesized. Spontaneous Ca2+ oscillations (SCOs) of cortical neurons were used for in vitro phenotypic screening. Maximal electroshock test (MES) and pentylenetetrazole (PTZ) test were used to access their anticonvulsant activity, and rotarod test was used to estimate their neurotoxicity. The active compounds in in vitro model are specifically effective in pentylenetetrazole (PTZ)-induced epilepsy model but not maximal electroshock (MES) model, more importantly with lower neurotoxicity as compared to commonly used drugs. Among them, compound 5c and 5e showed significant anticonvulsant activities in PTZ-induced epilepsy model with ED50 values at 31.81 mg/kg and 40.95 mg/kg, respectively. These compounds have improved neurotoxicity with protective index (PI = TD50/ED50) values at 17.22 and 9.09, respectively. Finally we demonstrated that compound 5c and 5e mainly acted on GABAA receptor as positive modulators but not sodium channels. Thus the present study has provided potential candidates for further investigation in epilepsy.
- Huang, Longjiang,Ding, Jing,Li, Min,Hou, Zhipeng,Geng, Yanru,Li, Xiufen,Yu, Haibo
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- A Direct approach to a 6-hetarylamino[1,2,4]triazolo[4,3-b][1,2,4,5] tetrazine library
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The synthesis of 6-hetarylamino[1,2,4]triazolo[4,3-b]-[1,2,4,5]tetrazines is reported. The functionalized secondary amines were constructed via a K 2CO3-mediated SNAr reaction of weakly basic hetarylamines with 3-(3,5-dimethylpyrazol-1-yl)[1,2,4]triazolo[4,3-b]-[1,2,4,5]tetrazines, which allowed displacement 3,5-dimethylpyrazolyl leaving group. Significantly, the reaction exhibited a broad substrate scope and proceeded in good yields.
- Palysaeva, Nadezhda V.,Kumpan, Katerina P.,Struchkova, Marina I.,Dalinger, Igor L.,Kormanov, Aleksandr V.,Aleksandrova, Nataly S.,Chernyshev, Victor M.,Pyreu, Dmitrii F.,Suponitsky, Kyrill Yu.,Sheremetev, Aleksei B.
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supporting information
p. 406 - 409
(2014/04/03)
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- A structure-activity relationship study of 1,2,4-triazolo[1,5-a][1,3,5] triazin-5,7-dione and its 5-thioxo analogues on anti-thymidine phosphorylase and associated anti-angiogenic activities
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Thirty-three 1,2,4-triazolo[1,5-a][1,3,5]triazin-5,7-dione and its 5-thioxo analogues were designed and synthesized which contained different substituents at meta- and/or para-positions of 2-phenyl or 2-benzyl ring attached to the fused ring structure. Th
- Bera, Hriday,Tan, Bee Jen,Sun, Lingyi,Dolzhenko, Anton V.,Chui, Wai-Keung,Chiu, Gigi Nagar Chee
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p. 325 - 334
(2013/10/01)
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- Synthesis of amino-1,2,4-triazoles by reductive ANRORC rearrangements of 1,2,4-oxadiazoles
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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
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p. 8724 - 8727
(2011/03/19)
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- 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
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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
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p. 429 - 436
(2008/02/09)
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- Triazole derivative and pharmaceutical use thereof
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An agent for the prophylaxis and treatment of immune-related diseases, in particular, immunosuppressant, an agent for the prophylaxis and treatment of allergic diseases, an agent for the prophylaxis and treatment of eosinophil-related diseases and an eosinophilia inhibitor, comprising, as an active ingredient, a series of triazole derivatives of the following formula (I) STR1 or the following formula (III) STR2 wherein each symbol is as defined in the specification, or a pharmaceutically acceptable salt thereof. A novel monocyclic or bicyclic triazole derivative. The agent for the prophylaxis and treatment of immune-related diseases, in particular, immunosuppressant, the agent for the prophylaxis and treatment of allergic diseases, the agent for the prophylaxis and treatment of eosinophil-related diseases, the eosinophilia inhibitor and the novel triazole derivative of the present invention all, have superior eosinophilia-inhibitory action and lymphocyte activation-inhibitory action. They are low toxic and persistent in action. They are particularly effective in the treatment of accumulation and activation of eosinophil and lymphocytes, inflammatory respiratory tract diseases, eosinophil-related diseases such as eosinophilia, and immune-related diseases.
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- Synthesis and pharmacological activity of triazolo[1,5-α]triazine derivatives inhibiting eosinophilia
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In continuation of our previous work on eosinophilia inhibitors, we synthesized an additional series of inhibitors, which consisted of 5-amino- 1-[(methylamino)thiocarbonyl]-1H-1,2,4-triazole derivatives and a newly developed series of 1,2,4-triazolo[1,5-
- Akahoshi, Fumihiko,Takeda, Shinji,Okada, Takehiro,Kajii, Masahiko,Nishimura, Hiroko,Sugiura, Masanori,Inoue, Yoshihisa,Fukaya, Chikara,Naito, Youichiro,Imagawa, Takashi,Nakamura, Norifumi
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p. 2985 - 2993
(2007/10/03)
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