336877-72-6Relevant academic research and scientific papers
Beyond Basicity: Discovery of Nonbasic DENV-2 Protease Inhibitors with Potent Activity in Cell Culture
Kühl, Nikos,Leuthold, Mila M.,Behnam, Mira A. M.,Klein, Christian D.
supporting information, p. 4567 - 4587 (2021/05/06)
The viral serine protease NS2B-NS3 is one of the promising targets for drug discovery against dengue virus and other flaviviruses. The molecular recognition preferences of the protease favor basic, positively charged moieties as substrates and inhibitors, which leads to pharmacokinetic liabilities and off-target interactions with host proteases such as thrombin. We here present the results of efforts that were aimed specifically at the discovery and development of noncharged, small-molecular inhibitors of the flaviviral proteases. A key factor in the discovery of these compounds was a cellular reporter gene assay for the dengue protease, the DENV2proHeLa system. Extensive structure-activity relationship explorations resulted in novel benzamide derivatives with submicromolar activities in viral replication assays (EC50 0.24 μM), selectivity against off-target proteases, and negligible cytotoxicity. This structural class has increased drug-likeness compared to most of the previously published active-site-directed flaviviral protease inhibitors and includes promising candidates for further preclinical development.
A New Class of Dengue and West Nile Virus Protease Inhibitors with Submicromolar Activity in Reporter Gene DENV-2 Protease and Viral Replication Assays
Kühl, Nikos,Graf, Dominik,Bock, Josephine,Behnam, Mira A. M.,Leuthold, Mila-Mareen,Klein, Christian D.
supporting information, p. 8179 - 8197 (2020/09/21)
Dengue and West Nile virus are rapidly spreading global pathogens for which no specific therapeutic treatments are available. One of the promising targets for drug discovery against dengue and other flaviviruses is the viral serine protease NS2B-NS3. We present the design, synthesis, and in vitro and cellular characterization of a novel chemotype of potent small-molecule non-peptidic dengue protease inhibitors derived from 4-benzyloxyphenylglycine. A newly developed luciferase-based DENV-2 protease reporter system in HeLa cells (DENV2proHeLa) was employed to determine the activity of the compounds in a cellular environment. Specificity and selectivity of the DENV2proHeLa system were confirmed by viral titer reduction assays. The compounds reach low micromolar to upper nanomolar inhibitory potency in cell-based assays, are selective against other serine proteases, and do not show relevant cytotoxicity. An extensive structure-activity relationship study provides a perspective for further drug development against flaviviral infections.
Discovery of Nanomolar Dengue and West Nile Virus Protease Inhibitors Containing a 4-Benzyloxyphenylglycine Residue
Behnam, Mira A. M.,Graf, Dominik,Bartenschlager, Ralf,Zlotos, Darius P.,Klein, Christian D.
, p. 9354 - 9370 (2015/12/23)
The dengue virus (DENV) and West Nile Virus (WNV) NS2B-NS3 proteases are attractive targets for the development of dual-acting therapeutics against these arboviral pathogens. We present the synthesis and extensive biological evaluation of inhibitors that
BETA-LACTAM COMPOUNDS, PROCESS FOR REPODUCING THE SAME AND SERUM CHOLESTEROL-LOWERING AGENTS CONTAINING THE SAME
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Page/Page column 45, (2010/02/07)
The compounds have the following general formula (I): [wherein: A1, A3 and A4 are hydrogen atom, halogen atom, alkyl group having one to five carbon atoms, alkoxy group having one to five carbon atoms, -COOR1, a following formula (wherein: R1 is hydrogen atom or alkyl group having one to five carbon atoms) or a following formula [wherein: R2 is -CH2OH group, -CH2OC(O)-R1 group or -CO2-R1 group; R3 is -OH group or-OC(O)-R1 group; R4 is -(CH2)kR5(CH2)1- (k and 1 are 0 or 1 more integer; k+1 is 10 or fewer integer); R5 means bond (single bond (-), -CH=CH-, -OCH2-, carbonyl group or -CH(OH)-.]. One of A1, A3 and A4 in formula (I) is must be the group in above mentioned formula (a). A2 is alkyl chain having one to five carbon atoms, alkoxy chain having one to five carbon atoms, alkenyl chain having one to five carbon atoms, hydroxyalkyl chain having one to five carbon atoms or carbonylalkyl chain having one to five carbon atoms. n, p, q or r are 0, 1 or 2.] or their pharmaceutical acceptable salts.
New proctolin analogues modified by the novel D-or L-phenylglycine derivatives. Synthesis and biological studies
Szeszel-Fedorowicz,Lisowski,Rosinski,Issberner,Osborne,Konopinska
, p. 411 - 417 (2007/10/03)
New analogues of insect neuromodulator proctolin (H-Arg-Tyr-Leu-Pro-Thr-OH), modified in position 2 of the peptide chain by L-or D-phenylglycine and its 4-substituted derivatives were synthesized. For modification of proctolin a series of novel L-or D-phenylglycine derivatives H-Phg(4-NO2)-OH (1), Boc-Phg(4-NO2)-OH (2), Boc-Phg(4-Me2N)-OH (3), H-Phg(4-OBzl)-OH (4), Boc-Phg(4-OBzl)-OH (5), H-D-Phg(4-NO2)-OH (6), Boc-D-Phg(4-NO2,)-OH (7), Boc-D-Phg(4-Me2N)-OH (8), were used. The following proctolin analogues were synthesized: H-Arg-Phg-Leu-Pro-Thr-OH (9), H-Arg-D-Phg-Leu-Pro-Thr-OH (10), H-Arg-Phg(4-OH)-Leu-Pro-Thr-OH (11), H-Arg-D-Phg(4-OH)-Leu-Pro-Thr-OH (12), H-Arg-Phg(4-NO2)-Leu-Pro-Thr-OH (13), H-Arg-D-Phg(4-NO2)-Leu-Pro-Thr-OH (14), H-Arg-Phg(4-NH2)-Leu-Pro-Thr-OH (15), H-Arg-D-Phg(4-NH2)-Leu-Pro-Thr-OH (16), H-Arg-Phg(4-NMe2)-Leu-Pro-Thr-OH (17), H-Arg-D-Phg(4-NMe2)-Leu-Pro-Thr-OH (18). Myotropic activity of proctolin analogues 9-18 was assayed in vitro on the semi-isolated heart of the mealworm Tenebrio molitor and on the foregut of the locust Schistocerca gregaria. All analogues showed a weak or none activity.
