- Salicylanilides Reduce SARS-CoV-2 Replication and Suppress Induction of Inflammatory Cytokines in a Rodent Model
-
SARS-CoV-2 virus has recently given rise to the current COVID-19 pandemic where infected individuals can range from being asymptomatic, yet highly contagious, to dying from acute respiratory distress syndrome. Although the world has mobilized to create antiviral vaccines and therapeutics to combat the scourge, their long-term efficacy remains in question especially with the emergence of new variants. In this work, we exploit a class of compounds that has previously shown success against various viruses. A salicylanilide library was first screened in a SARS-CoV-2 activity assay in Vero cells. The most efficacious derivative was further evaluated in a prophylactic mouse model of SARS-CoV-2 infection unveiling a salicylanilide that can reduce viral loads, modulate key cytokines, and mitigate severe weight loss involved in COVID-19 infections. The combination of anti-SARS-CoV-2 activity, cytokine inhibitory activity, and a previously established favorable pharmacokinetic profile for the lead salicylanilide renders salicylanilides in general as promising therapeutics for COVID-19.
- Beutler, Nathan,Blake, Steven,Eubanks, Lisa M.,Janda, Kim D.,Ji, Henry,Manning, John T.,Maruyama, Junki,Paessler, Slobodan,Shaabani, Namir,Teijaro, John R.
-
p. 2229 - 2237
(2021/08/24)
-
- Novel propargylamine-based inhibitors of cholinesterases and monoamine oxidases: Synthesis, biological evaluation and docking study
-
A combination of several pharmacophores in one molecule has been successfully used for multi-target-directed ligands (MTDL) design. New propargylamine substituted derivatives combined with salicylic and cinnamic scaffolds were designed and synthesized as potential cholinesterases and monoamine oxidases (MAOs) inhibitors. They were evaluated in vitro for inhibition of acetyl- (AChE) and butyrylcholinesterase (BuChE) using Ellman's method. All the compounds act as dual inhibitors. Most of the derivatives are stronger inhibitors of AChE, the best activity showed 5-bromo-N-(prop-2-yn-1-yl)salicylamide 1e (IC50 = 8.05 μM). Carbamates (4-bromo-2-[(prop-2-yn-1-yl)carbamoyl]phenyl ethyl(methyl)carbamate 2d and 2,4-dibromo-6-[(prop-2-yn-1-yl)carbamoyl]phenyl ethyl(methyl)carbamate 2e were selective and the most active for BuChE (25.10 and 26.09 μM). 4-Bromo-2-[(prop-2-yn-1-ylimino)methyl]phenol 4a was the most potent inhibitor of MAOs (IC50 of 3.95 and ≈10 μM for MAO-B and MAO-A, respectively) along with a balanced inhibition of both cholinesterases being a real MTDL. The mechanism of action was proposed, and binding modes of the hits were studied by molecular docking on human enzymes. Some of the derivatives also exhibited antioxidant properties. In silico prediction of physicochemical parameters affirm that the molecules would be active after oral administration and able to reach brain tissue.
- Krátky, Martin,Vu, Quynh Anh,?těpánková, ?árka,Maruca, Annalisa,Silva, Tiago Barros,Ambro?, Martin,Pflégr, Václav,Rocca, Roberta,Svr?ková, Katarína,Alcaro, Stefano,Borges, Fernanda,Vin?ová, Jarmila
-
-
- Discovery of Novel Polycyclic Heterocyclic Derivatives from Evodiamine for the Potential Treatment of Triple-Negative Breast Cancer
-
Evodiamine (Evo) is a quinazolinocarboline alkaloid found in Evodia rutaecarpa and exhibits moderate antiproliferative activity. Herein, we report using a scaffold-hopping approach to identify a series of novel polycyclic heterocyclic derivatives based on Evo as the topoisomerase I (Top1) inhibitor for the treatment of triple-negative breast cancer (TNBC), which is an aggressive subtype of breast cancer with limited treatment options. The most potent compound 7f inhibited cell growth in a human breast carcinoma cell line (MDA-MB-231) with an IC50 value of 0.36 μM. Further studies revealed that Top1 was the target of 7f, which directly induced irreversible Top1-DNA covalent complex formation or induced an oxidative DNA lesion through an indirect mechanism mediated by reactive oxygen species. More importantly, in vivo studies showed that 7f exhibited potent antitumor activity in a TNBC-patient-derived tumor xenograft model. These results suggest that compound 7f deserves further investigation as a promising candidate for the treatment of TNBC.
- Chen, Zhe-Sheng,Li, Dahong,Qiu, Yangyi,Wu, Liang,Xu, Jinyi,Xu, Shengtao,Yang, Dong-Hua,Yao, Hong,Zhou, Manzhen
-
p. 17346 - 17365
(2021/12/09)
-
- Salicylanilide Analog Minimizes Relapse of Clostridioides difficile Infection in Mice
-
Clostridioides difficile infection (CDI) causes serious and sometimes fatal symptoms like diarrhea and pseudomembranous colitis. Although antibiotics for CDI exist, they are either expensive or cause recurrence of the infection due to their altering the colonic microbiota, which is necessary to suppress the infection. Here, we leverage a class of known membrane-targeting compounds that we previously showed to have broad inhibitory activity across multiple Clostridioides difficile strains while preserving the microbiome to develop an efficacious agent. A new series of salicylanilides was synthesized, and the most potent analog was selected through an in vitro inhibitory assay to evaluate its pharmacokinetic parameters and potency in a CDI mouse model. The results revealed reduced recurrence of CDI and diminished disturbance of the microbiota in mice compared to standard-of-care vancomycin, thus paving the way for novel therapy that can potentially target the cell membrane of C. difficile to minimize relapse in the recovering patient.
- Blake, Steven,Thanissery, Rajani,Rivera, Alissa J.,Hixon, Mark S.,Lin, Mingliang,Theriot, Casey M.,Janda, Kim D.
-
p. 6898 - 6908
(2020/07/28)
-
- Halogen Bonding Increases the Potency and Isozyme Selectivity of Protein Arginine Deiminase 1 Inhibitors
-
Protein arginine deiminases (PADs) hydrolyze the side chain of arginine to form citrulline. Aberrant PAD activity is associated with rheumatoid arthritis, multiple sclerosis, lupus, and certain cancers. These pathologies established the PADs as therapeutic targets and multiple PAD inhibitors are known. Herein, we describe the first highly potent PAD1-selective inhibitors (1 and 19). Detailed structure–activity relationships indicate that their potency and selectivity is due to the formation of a halogen bond with PAD1. Importantly, these inhibitors inhibit histone H3 citrullination in HEK293TPAD1 cells and mouse zygotes with excellent potency. Based on this scaffold, we also developed a PAD1-selective activity-based probe that shows remarkable cellular efficacy and proteome selectivity. Based on their potency and selectivity we expect that 1 and 19 will be widely used chemical tools to understand PAD1 biology.
- Mondal, Santanu,Gong, Xuefeng,Zhang, Xiaoqian,Salinger, Ari J.,Zheng, Li,Sen, Sudeshna,Weerapana, Eranthie,Zhang, Xuesen,Thompson, Paul R.
-
supporting information
p. 12476 - 12480
(2019/08/07)
-
- Scaffold Diversity Inspired by the Natural Product Evodiamine: Discovery of Highly Potent and Multitargeting Antitumor Agents
-
A critical question in natural product-based drug discovery is how to translate the product into drug-like molecules with optimal pharmacological properties. The generation of natural product-inspired scaffold diversity is an effective but challenging strategy to investigate the broader chemical space and identify promising drug leads. Extending our efforts to the natural product evodiamine, a diverse library containing 11 evodiamine-inspired novel scaffolds and their derivatives were designed and synthesized. Most of them showed good to excellent antitumor activity against various human cancer cell lines. In particular, 3-chloro-10-hydroxyl thio-evodiamine (66c) showed excellent in vitro and in vivo antitumor efficacy with good tolerability and low toxicity. Antitumor mechanism and target profiling studies indicate that compound 66c is the first-in-class triple topoisomerase I/topoisomerase II/tubulin inhibitor. Overall, this study provided an effective strategy for natural product-based drug discovery. (Figure Presented).
- Wang, Shengzheng,Fang, Kun,Dong, Guoqiang,Chen, Shuqiang,Liu, Na,Miao, Zhenyuan,Yao, Jianzhong,Li, Jian,Zhang, Wannian,Sheng, Chunquan
-
p. 6678 - 6696
(2015/09/07)
-
- Design, synthesis, and biological activities of closantel analogues: Structural promiscuity and its impact on onchocerca volvulus
-
Onchocerciasis, or river blindness, is a neglected tropical disease that affects more than 37 million people worldwide, primarily in Africa and Central and South America. We have disclosed evidence that the larval-stage-specific chitinase, OvCHT1, may be a potential biological target for affecting nematode development. On the basis of screening efforts, closantel, a known anthelmintic drug, was discovered as a potent and highly specific OvCHT1 inhibitor. Originally, closantel's anthelmintic mode of action was believed to rely solely on its role as a proton ionophore; thus, the impact of each of its biological activities on O. volvulus L3moltingwas investigated. Structure-activity relationship studies on an active closantel fragment are detailed, and remarkably, by use of a simple salicylanilide scaffold, compounds acting only as protonophores or chitinase inhibitors were identified. From these data, unexpected synergistic protonophore and chitinase inhibition activities have also been found to be critical for molting in O. volvulus L3 larvae.
- Garner, Amanda L.,Gloeckner, Christian,Tricoche, Nancy,Zakhari, Joseph S.,Samje, Moses,Cho-Ngwa, Fidelis,Lustigman, Sara,Janda, Kim D.
-
experimental part
p. 3963 - 3972
(2011/08/05)
-
- Discovery and structure-activity relationships of modified salicylanilides as cell permeable inhibitors of poly(ADP-ribose) glycohydrolase (PARG)
-
The metabolism of poly(ADP-ribose) (PAR) in response to DNA strand breaks, which involves the concerted activities of poly(ADP-ribose) polymerases (PARPs) and poly(ADP-ribose) glycohydrolase (PARG), modulates cell recovery or cell death depending upon the level of DNA damage. While PARP inhibitors show high promise in clinical trials because of their low toxicity and selectivity for BRCA related cancers, evaluation of the therapeutic potential of PARG is limited by the lack of well-validated cell permeable inhibitors. In this study, target-related affinity profiling (TRAP), an alternative to high-throughput screening, was used to identify a number of druglike compounds from several chemical classes that demonstrated PARG inhibition in the low-micromolar range. A number of analogues of one of the most active chemotypes were synthesized to explore the structure-activity relationship (SAR) for that series. This led to the discovery of a putative pharmacophore for PARG inhibition that contains a modified salicylanilide structure. Interestingly, these compounds also inhibit PARP-1, indicating strong homology in the active sites of PARG and PARP-1 and raising a new challenge for development of PARG specific inhibitors. The cellular activity of a lead inhibitor was demonstrated by the inhibition of both PARP and PARG activity in squamous cell carcinoma cells, although preferential inhibition of PARG relative to PARP was observed. The ability of inhibitors to modulate PAR metabolism via simultaneous effects on PARPs and PARG may represent a new approach for therapeutic development.
- Steffen, Jamin D.,Coyle, Donna L.,Damodaran, Komath,Beroza, Paul,Jacobson, Myron K.
-
experimental part
p. 5403 - 5413
(2011/10/02)
-
- Pharmaceutical Compositions Comprising Nitrogen-Containing Fused Ring Coumpounds
-
[Problems] The present invention provides pharmaceutical composition which is effective for the prophylaxis or treatment of pathology showing involvement of uric acid (hyperuricemia, gouty tophus, acute gout arthritis, chronic gout arthritis, gouty kidney, urolithiasis, renal function disorder, coronary arterial disease, ischemic heart disease and the like) and the like, and is superior in the time-course stability and dissolution property (disintegration property). [Solving Means] The pharmaceutical composition of the present invention is a pharmaceutical composition comprising a nitrogen-containing fused ring compound represented by the following formula [1] or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable additives, wherein the nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof is not in contact with a basic additive: wherein each symbol is as described in the specification.
- -
-
-
- Identification of halosalicylamide derivatives as a novel class of allosteric inhibitors of HCV NS5B polymerase
-
Halosalicylamide derivatives were identified from high-throughput screening as potent inhibitors of HCV NS5B polymerase. The subsequent structure and activity relationship revealed the absolute requirement of the salicylamide moiety for optimum activity. Methylation of either the hydroxyl group or the amide group of the salicylamide moiety abolished the activity while the substitutions on both phenyl rings are acceptable. The halosalicylamide derivatives were shown to be non-competitive with respect to elongation nucleotide and demonstrated broad genotype activity against genotype 1-3 HCV NS5B polymerases. Inhibitor competition studies indicated an additive binding mode to the initiation pocket that is occupied by the thiadiazine class of compounds and an additive binding mode to the elongation pocket that is occupied by diketoacids, but a mutually exclusive binding mode with respect to the allosteric thumb pocket that is occupied by the benzimidazole class of inhibitors. Therefore, halosalicylamides represent a novel class of allosteric inhibitors of HCV NS5B polymerase.
- Liu, Yaya,Donner, Pamela L.,Pratt, John K.,Jiang, Wen W.,Ng, Teresa,Gracias, Vijaya,Baumeister, Steve,Wiedeman, Paul E.,Traphagen, Linda,Warrior, Usha,Maring, Clarence,Kati, Warren M.,Djuric, Stevan W.,Molla, Akhteruzzaman
-
scheme or table
p. 3173 - 3177
(2009/04/11)
-
- Production Method of Nitrogen-Containing Fused Ring Compounds
-
[Problems] The present invention provides a superior production method and a superior purification method of compounds effective for the treatment or prophylaxis of pathology showing involvement of uric acid, such as hyperuricemia, gouty tophus, acute gouty arthritis, chronic gouty arthritis, gouty kidney, urolithiasis, renal function disorder, coronary artery disease, ischemic heart disease and the like. [Means] A compound represented by the following formula [2] or a pharmaceutically acceptable salt thereof can be produced by reacting a compound represented by the following formula [3] or a salt thereof with a compound represented by the following formula [4], a salt thereof or a reactive derivative thereof. Moreover, crystallization of a compound represented by the formula [2] can be performed with industrially superior workability, and high quality crystals of a compound represented by the formula [2] can be obtained. wherein each symbol is as defined in the description.
- -
-
Page/Page column 56
(2010/11/30)
-
- Nitrogen-containing fused ring compounds and use thereof
-
A URAT1 activity inhibitor containing a nitrogen-containing fused ring compound represented by the following formula [1]: wherein each symbol is as defined in the description. The present invention is useful for the prophylaxis or treatment of pathology showing involvement of uric acid, such as hyperuricemia, gouty tophus, acute gouty arthritis, chronic gouty arthritis, gouty kidney, urolithiasis, renal function disorder, coronary artery disease, ischemic heart disease and the like.
- -
-
Page/Page column 93
(2010/11/25)
-
- Synthetic study of substituted arylsulfonylphenylbenzamides
-
For the structure-activity relationship, a series of substituted arylsulfonyl-phenylbenzamides is reported.
- Gong, Denghuang,Li, Jiafeng,Yuan, Chengye,Yuan, Junying
-
-
- Urea thiadiazole inhibitors of plasminogen activator inhibior-1
-
Methods of treating disorders associated with elevated levels of PAI-1 are disclosed comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of formula (I), or a pharmaceutically-acceptable salt, prodrug, stereoisomer or solvate thereof, wherein: A is aryl o heteroaryl, and R1-R12, are defined herein. The invention also pertains to pharmaceutical compositions and compounds within the scope of formula (I) as well as medicaments and articles of manufacture comprising compounds of formula (I).
- -
-
Page/Page column 14
(2010/02/11)
-
- Amide thiadiazole inhibitors of plasminogen activator inhibitor-1
-
Methods of treating disorders associated with elevated levels of PAI-1 are disclosed comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of formula at least one compound of formula (I), or a ph
- -
-
Page/Page column 14; 15
(2010/02/12)
-
- Acyl derivatives of 2-aminobenzimidazole and their fungicide activity
-
Procedures have been developed for the preparation of methyl 2-benzimidazolylcarbamate, 2-acetylaminobenzimidazole, 2- benzoylaminobenzimidazole, 2-(3,5-dibromo-2-hydroxybenzoylamino)benzimidazole, 1-(3,6-dichloro-2-methoxybenzoyl)-2-aminobenzimidazole, 2-(3,5-dichloro-2- hydroxybenzoylamino)benzimidazole, 2-(3,5-dichloro-2-methoxybenzoylamino) benzimidazole, and 1-(3,5,6-trichloro-2-methoxybenzoyl)-2-aminobenzimidazole. The synthesized compounds have been tested for fungicide activity.
- Pilyugin,Sapozhnikov,Sapozhnikova
-
p. 738 - 743
(2007/10/03)
-
- Substituted salicylanilides as inhibitors of two-component regulatory systems in bacteria
-
A new class of inhibitors of the two-component regulatory systems (TCS) of bacteria was discovered based on the salicylanilide screening hits, closantel (1) and tetrachlorosalicylanilide (9). A systematic SAR study versus a model TCS, KinA/Spo0F, demonstrated the importance of electron- attracting substituents in the salicyloyl ring and hydrophobic groups in the anilide moiety for optimal activity. In addition, derivatives 8 and 16, containing the 2,3-dihydroxybenzanilide structural motif, were potent inhibitors of the autophosphorylation of the KinA kinase, with IC50s of 2.8 and 6.3 μM, respectively. Compound 8 also inhibited the TCS mediating vancomycin resistance (VanS/VanR) in a genetically engineered Enterococcus faecalis cell line at concentrations subinhibitory for growth. Closantel (1), tetrachlorosalicylanilide (9), and several related derivatives (2, 7, 10, 11, 20) had antibacterial activity against the drug-resistant organisms, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF).
- Macielag, Mark J.,Demers, James P.,Fraga-Spano, Stephanie A.,Hlasta, Dennis J.,Johnson, Sigmond G.,Kanojia, Ramesh M.,Russell, Ronald K.,Sui, Zhihua,Weidner-Wells, Michele A.,Werblood, Harvey,Foleno, Barbara D.,Goldschmidt, Raul M.,Loeloff, Michael J.,Webb, Glenda C.,Barrett, John F.
-
p. 2939 - 2945
(2007/10/03)
-
- Synthesis and potential anthelmintic activity of methyl-5-(4-salicyloyl-piperazin-1-yl)-benzimidazole-2-carbamates
-
A series of methyl-5-(4-salicyloyl-piperazin-1-yl)-benzimidazole-2-carbamates (IX) has been prepared. 5-(4-salicyloyl-piperazin-1-yl)-2-nitro anilines (VII) have been synthesized starting from 5-piperazino-2-nitro anilines and salicyloyl chlorides. Catalytic reduction of VII with Pd/C, followed by treatment with 1,3-dicarbomethoxy-S-methyl isothiourea, yielded the corresponding carbamates (IX), the anthelmintic activity of which was studied. Compound IX(a) significantly reduced the numbers of preadults, adults and encysted T. spiralis larvae in experimental mice.
- Ravina,Sanchez-Alonso,Fueyo,Baltar,Bos,Iglesias,Sanmartin
-
p. 689 - 694
(2007/10/02)
-
- SYNTHESIS OF ACYL CHLORIDES OF 3-CHLORO-, 5-CHLORO-, AND 3,5-DICHLORO-2-HYDROXYBENZOIC ACIDS.
-
Acyl halides of chloro-substituted hydroxybenzoic acids (CSHBA) are used as intermediates for production of amides, anilides, and esters having high pesticidal activity. The reactions of alkali salts of 3-chloro-, 5-chloro-, and 3,5-dichloro-2-hydroxybenzoic acids with thionyl chloride for synthesis of any chlorides were studied. The influence of temperature and initial component ratio was studied. On the basis of experimental results, optimal conditions are suggested.
- Shakirov,Teplov,Bikkulov
-
p. 423 - 425
(2007/10/02)
-