- A combined experimental and in silico characterization to highlight additional structural features and properties of a potentially new drug
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LASSBio-1755 is a new cycloalkyl-N-acylhydrazone parent compound designed for the development of derivatives with antinociceptive and anti-inflammatory activities. Although single crystal X-ray diffraction has been considered as the golden standard in structure determination, we successfully used X-ray powder diffraction data in the structural determination of new synthesized compounds, in order to overcome the bottle-neck due to the difficulties experienced in harvesting good quality single crystals of the compounds. We therefore unequivocally assigned the relative configuration (E) to the imine double bond and a s-cis conformation of the amide function of the N-acylhydrazone compound. These features are confirmed by a computational analysis performed on the basis of molecular dynamics calculations, which are extended not only to the structural characteristics but also to the analysis of the anisotropic atomic displacement parameters, a further information – missed in a typical powder diffraction analysis. The so inferred data were used to perform additional cycles of refinement and eventually generate a new cif file with additional physical information. Furthermore, crystal morphology prediction was performed, which is in agreement with the experimental images acquired by scanning electron microscopy, thus providing useful information on possible alternative paths for better crystallization strategies.
- Bastos, Isadora T.S.,Costa, Fanny N.,Silva, Tiago F.,Barreiro, Eliezer J.,Lima, Lídia M.,Braz, Delson,Lombardo, Giuseppe M.,Punzo, Francesco,Ferreira, Fabio F.,Barroso, Regina C.
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- Design and synthesis in silico drug-like prediction and pharmacological evaluation of cyclopolymethylenic homologous of lassbio-1514
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Acylhydrazones are still an important framework to the design of new bioactive com-pounds. As treatment of chronic pain represents a clinical challenge, we decided to modify the structure of LASSBio-1514 (1), previously described as anti-inflammatory and analgesic proto-type. Applying the homologation as a strategy for molecular modification, we designed a series of cyclopentyl-(2a–e), cyclobutyl-(3a–e), and cyclopropylacylhydrazones (4a–e) that were synthetized and evaluated in murine models of inflammation and pain. A comparison of their in silico physico-chemical and drug-like profile was conducted, as well as their anti-inflammatory and analgesic effect. Compounds 4a (LASSBio-1755) and 4e (LASSBio-1757) displayed excellent in silico drug-like profiles and were identified as new analgesic lead-candidates in acute and chronic model of pain, through oral administration.
- Alexandre-Moreira, Magna Suzana,Aparecida-Silva, Cristiane,Barreiro, Eliezer J.,Bispo Júnior, Walfrido,Lima, Lidia Moreira,Zapata-Sudo, Gisele,da Silva Monteiro, Carlos Eduardo,da Silva, Tiago Fernandes,de Queiroz, Aline Cavalcanti
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- Growth Factor Receptor antagonists. Preparation method and application thereof
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The invention relates to a small molecule antagonist for transforming growth factor β receptors, a method for preparing the small molecule antagonist, and application of the small molecule antagonist in preparation of drugs. The small molecule antagonist for transforming the growth factor β receptor has the application of treating and/or preventing various diseases mediated by ALK5, and has great clinical application potential.
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Paragraph 0263-0268
(2021/11/27)
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- Bioisosteric Replacement of Arylamide-Linked Spine Residues with N-Acylhydrazones and Selenophenes as a Design Strategy to Novel Dibenzosuberone Derivatives as Type i 1/2 p38α MAP Kinase Inhibitors
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The recent disclosure of type I 1/2 inhibitors for p38α MAPK demonstrated how the stabilization of the R-spine can be used as a strategy to greatly increase the target residence time (TRT) of inhibitors. Herein, for the first time, we describe N-acylhydrazone and selenophene residues as spine motifs, yielding metabolically stable inhibitors with high potency on enzymatic, NanoBRET, and whole blood assays, improved metabolic stability, and prolonged TRT.
- Pedreira, Júlia G. B.,Nahidino, Philipp,Kudolo, Mark,Pantsar, Tatu,Berger, Benedict-Tilman,Forster, Michael,Knapp, Stefan,Laufer, Stefan,Barreiro, Eliezer J.
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supporting information
p. 7347 - 7354
(2020/09/11)
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- COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH APJ RECEPTOR ACTIVITY
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This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt and/or hydrate and/or prodrug of the compound) that modulate (e.g., agonize) the apelin receptor (also referred to herein as the APJ receptor; gene symbol "APLNR"). This disclosure also features compositions containing the same as well as other methods of using and making the same. The chemical entities are useful, e.g., for treating a subject (e.g., a human) having a disease, disorder, or condition in which a decrease in APJ receptor activity (e.g., repressed or impaired APJ receptor signaling; e.g., repressed or impaired apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathology and/or symptoms and/or progression of the disease, disorder, or condition. Non-limiting examples of such diseases, disorders, or conditions include: (i) cardiovascular disease; (ii) metabolic disorders; (iii) diseases, disorders, and conditions associated with vascular pathology; and (iv) organ failure; (v) diseases, disorders, and conditions associated with infections (e.g., microbial infections); and (vi) diseases, disorders, or conditions that are sequela or comorbid with any of the foregoing or any disclosed herein. More particular non-limiting examples of such diseases, disorders, or conditions include pulmonary hypertension (e.g., PAH); heart failure; type II diabetes; renal failure; sepsis; and systemic hypertension.
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Page/Page column 161-162
(2019/09/18)
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- Discovery of SHR1653, a Highly Potent and Selective OTR Antagonist with Improved Blood-Brain Barrier Penetration
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The oxytocin receptor (OTR) plays a major role in the control of male sexual responses. Antagonists of the OTR have been reported to inhibit ejaculation in animal models and serve as a potential treatment for premature ejaculation (PE). Herein, we describe a novel scaffold featuring an aryl substituted 3-azabicyclo [3.1.0] hexane structure. The lead compound, SHR1653, was shown to be a highly potent OTR antagonist, which exhibited excellent selectivity over V1AR, V1BR, and V2R. This novel molecule was shown to have a favorable pharmacokinetic profile across species, as well as robust in vivo efficacy in a rat uterine contraction model. Interestingly, SHR1653 exhibited excellent blood-brain barrier penetration, which might be beneficial for the treatment of CNS-related PE.
- Li, Xin,Zhang, Zhigao,Chen, Yang,Wan, Hong,Sun, Jiakang,Wang, Bin,Feng, Bingqiang,Hu, Bing,Shi, Xingxing,Feng, Jun,Zhang, Lei,He, Feng,Bai, Chang,Zhang, Lianshan,Tao, Weikang
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supporting information
p. 996 - 1001
(2019/06/21)
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- Synthesis, Dissociation Constants, and Antimicrobial Activity of Novel 2,3-Disubstituted-1,3-thiazolidin-4-one Derivatives
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In this article, a new series of 2,3-disubstituted-1,3-thiazolidin-4-one derivatives have been designed, synthesized, and evaluated as antimicrobial agents. New compounds were prepared by the cyclization reaction of N-substituted carboxylic acid hydrazide derivatives with mercaptoacetic acid. The structures of the obtained compounds were confirmed by means of IR, 1H NMR, and 13C NMR spectra. The dissociation constants were determined using spectrophotometric method. All synthesized compounds were tested for their in vitro antibacterial and antifungal activities using the broth microdilution method.
- Popiolek, Lukasz,Stefaska, Joanna,Kielczykowska, Malgorzata,Musik, Irena,Biernasiuk, Anna,Malm, Anna,Wujec, Monika
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p. 393 - 402
(2016/04/19)
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- Synthesis of 3-hydroxyindanones via potassium salt of amino acid catalyzed regioselective intramolecular aldolization of ortho-diacylbenzenes
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First organocatalytic intramolecular aldolization of ortho-diacylbenzenes to construct highly functionalized 3-hydroxyindanones is described. In this transformation a high trans-selectivity is achieved by the use of metal salt of amino acid. This method allows an easy access to the strained spirocyclic 3-hydroxyindanones related to a number of natural product frameworks. Synthesis of a new class of indole skeleton substituted by 3-hydroxyindanones added an extra essence to this new protocol.
- Chanda, Tanmoy,Chowdhury, Sushobhan,Anand, Namrata,Koley, Suvajit,Gupta, Ashutosh,Singh, Maya Shankar
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supporting information
p. 981 - 985
(2015/03/04)
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- One-pot synthesis of 3,4,5-trisubstituted 1,2,4-triazoles via the addition of hydrazides to activated secondary amides
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A general approach has been developed for the one-pot synthesis of 3,4,5-trisubstituted 1,2,4-triazoles from secondary amides and hydrazides via triflic anhydride activation followed by microwave-induced cyclodehydration. In addition, the 1,2,4-triazole moiety is shown to be a useful directing group for Ru-catalyzed C-H arylation. Access to 1,2,4-triazolophenanthridine can be achieved from the reaction products using a Pd-catalyzed intramolecular C-H functionalization reaction.
- Bechara, William S.,Khazhieva, Inna S.,Rodriguez, Elsa,Charette, André B.
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supporting information
p. 1184 - 1187
(2015/03/14)
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- 5-SUBSTITUTED 2-(PHENYLMETHYL) THIO-4-PHENYL-4H-1,2,4-TRIAZOLE DERIVATIVES AND RELATED COMPOUNDS AS GABA-AGONISTS FOR THE TREATMENT OF URINARY INCONTINENCE AND RELATED DISEASES
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This invention relates to phenyltriazole derivatives of the formula (I) and salts thereof which is useful as an active ingredient of pharmaceutical preparations : (I) wherein R1 represents alkyl optionally substituted or 3-8 membered saturated or unsaturated ring optionally substituted, R2 represents -COR21, -(CH2)n-R21 or tert-butyl, X represents CR10R11, NR12, S, O, SO2, or SO wherein R10, R11 and R12 independently represent hydrogen or methyl. The other substituents are as defined in the claims. The phenyltriazole derivatives of the present invention have an excellent activity as GABAb agonist and are useful for the prophylaxis and treatment of diseases associated with GABAb activity, in particular for the treatment of overactive bladder, urinary incontinence such as urge urinary incontinence, benign prostatic hyperplasia (BPH), chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, neuralgia, neuropathies, algesia, or nerve injury.
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Page/Page column 39
(2008/06/13)
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- NOVEL KETO-OXADIAZOLE DERIVATIVES AS CATHEPSIN INHIBITORS
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Novel difluorinated amide derivatives of Formula (II) as inhibitors of cathepsin S, K, B, and L, the pharmaceutically acceptable salts and N-oxides thereof, their uses as therapeutic agents and the methods of their making.
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Page/Page column 46
(2008/06/13)
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- Antihypertensive actions of hydrazidones: Study of acylated dichloroarylhydrazones
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A series of acylated dichloroarylhydrazones has been prepared and evaluated on spontaneously hypertensive rats (SHR). The presence of 2-Cl and 6-Cl aromatic substituents in a clonidine like position is not required since derivatives bearing 2- and 4-chloro as well as 3- and 4-chloro substituents exert antihypertensive activities. Activity is also maintained in certain 2,6 disubstituted derivatives where one of the chlorine atoms is replaced by F or NO2.
- Cave,Galons,Miocque,Rinjard,Tran,Binet
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- Insecticidal 5-thiocarbamoyl-1,3,4-oxadiazoles
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Compounds of the formula: STR1 wherein R1 and R2 are independently lower alkyl having from 1 to 4 carbon atoms; and R3 is lower alkyl having from 1 to 6 carbon atoms, lower cycloalkyl having from 3 to 6 carbon atoms optionally substituted with methyl or ethyl, lower alkoxyalkyl having up to a total of 8 carbon atoms or lower alkylthioalkyl having up to a total of 8 carbon atoms are insecticidal.
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