Medicinal Chemistry Research最新文献

{"title":"Morpholinated curcuminoids against urinary bladder cancer cells: synthesis and anticancer evaluation","authors":"Pawel Bakun,&nbsp;Malgorzata Kucinska,&nbsp;Paulina Kobyłka,&nbsp;Joanna Kuźmińska,&nbsp;Tomasz Koczorowski,&nbsp;Dariusz T. Mlynarczyk,&nbsp;Lukasz Popenda,&nbsp;Katarzyna Górska,&nbsp;Małgorzata Kasperkowiak,&nbsp;Marek Murias,&nbsp;Anna Jelińska,&nbsp;Tomasz Goslinski","doi":"10.1007/s00044-024-03233-z","DOIUrl":"10.1007/s00044-024-03233-z","url":null,"abstract":"<div><p>Cancers present a significant medical problem despite the development of medical and pharmaceutical sciences leading to a search for further therapeutic approaches. One such approach could involve the use of curcumin or its derivatives. Curcumin reveals interesting antineoplastic effects that could help in the treatment of cancer diseases. However, this natural product possesses some limitations which prevent its application in medicine. Among its limitations, it is characterized by poor water solubility, low stability, and unsatisfactory bioavailability. Aiming to improve the pharmacokinetic properties and enhance the biological effects of curcumin, a series of 30 chemical compounds inspired by its structure was synthesized and characterized. New compounds were subjected to a preliminary MTT viability assessment of 5637 and SCaBER bladder cancer cell lines. Some derivatives revealed the cytotoxic activities already at the concentration of 1 µM. The most active compounds showed no significant acute toxicity in the Microtox test. Intracellular uptake on the basis of the fluorescent properties of the new compounds was analyzed. It was also found that the presence of the morpholine group in the structure improved the biological activity of studied curcumin derivatives. As selected compounds could be considered potential drug candidates, further studies are necessary towards recognition of the exact mechanism of cellular action, the in vivo stability, and toxicity.</p><div><figure><div><div><picture><source><img></source></picture></div><div><p>A series of 30 derivatives of curcumin was synthesized, characterized and subjected to a MTT viability assessment on 5637 and SCaBER bladder cancer cell lines. Some derivatives revealed the cytotoxic activities at the concentration of 1 µM. Compounds were subjected to acute toxicity study (Microtox test) and intracellular uptake analysis. The presence of the morpholine group in the structure was important for the biological activity of studied derivatives.</p></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 6","pages":"944 - 963"},"PeriodicalIF":2.6,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-024-03233-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141113321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and in vitro biological activity of chalcone derivatives as potential antiparasitic agents","authors":"Koketso J. Setshedi,&nbsp;Richard M. Beteck,&nbsp;Kayhan Ilbeigi,&nbsp;Dorien Mabille,&nbsp;Guy Caljon,&nbsp;Lesetja J. Legoabe","doi":"10.1007/s00044-024-03235-x","DOIUrl":"10.1007/s00044-024-03235-x","url":null,"abstract":"<div><p>Kinetoplastids are a group of flagellated protozoans including medically important parasites of the genus <i>Trypanosoma</i> and <i>Leishmania</i>. The corresponding diseases have afflicted humans for centuries. In an effort to combat kinetoplastid infections, a set of 21 chalcones was synthesized and evaluated for their in vitro anti-protozoal efficacy against <i>Trypanosoma brucei</i>, <i>Trypanosoma brucei rhodesiense</i>, <i>Trypanosoma cruzi</i>, and <i>Leishmania infantum</i>. To ensure safety, these compounds underwent a selectivity evaluation by assessing toxicity against a human lung fibroblast cell line. Compound <b>K4</b> exhibited remarkable and selective trypanocidal activity against <i>T. b. brucei</i> with IC₅₀ value of 0.31 ± 0.27 µM and <i>T. b. rhodesiense</i> with IC₅₀ value of 0.96 ± 0.86 µM. Compound <b>K9</b> also showed significant trypanocidal activity against <i>T. b. brucei</i> (IC₅₀: 0.45 ± 0.14 µM) and <i>T. b. rhodesiense</i> (IC₅₀: 0.93 ± 0.51 µM). In both compounds, electron withdrawing groups are appended to the styrenyl moiety.</p><div><figure><div><div><picture><img></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 6","pages":"977 - 988"},"PeriodicalIF":2.6,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-024-03235-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141118159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of HNPC-A188: a novel acaricide containing trifluoroethyl thioether and pyrimidin-4-amine","authors":"Ting Xiao,&nbsp;Aiping Liu,&nbsp;Xingping Liu,&nbsp;Fujun Zhong,&nbsp;Guojun Li,&nbsp;Zhichang Huang,&nbsp;Zai Zhang,&nbsp;Yeguo Ren,&nbsp;Jiang-Sheng Li,&nbsp;Weidong Liu","doi":"10.1007/s00044-024-03231-1","DOIUrl":"10.1007/s00044-024-03231-1","url":null,"abstract":"<div><p>Pyrimidifen is an excellent commercial acaricide, but it is not low toxic to mammals. Trifluoroethyl thioether derivatives exhibit excellent bioactivity, and flupentiofenox is the first commercially available trifluoroethyl thioether acaricide. To search for novel pesticides, we conducted research around pyrimidifen and flupentiofenox. By introducing trifluoroethyl thioether and F, Cl, CH₃ substituents at different positions on the benzene ring, we successfully introduced trifluoroethyl thioether into the pyrimidine derivatives. Further optimization resulted in compound <b>T7 (HNPC-A188)</b>(<i>5-chloro-6-(difluoromethyl)-N-(2-(2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)thio)phenoxy)ethyl)pyrimidin-4-amine</i>). <b>HNPC-A188</b> exhibits excellent acaricidal activity with LC₅₀ values of 0.19 mg/L against <i>Tetranychus urticae</i>, which can be compared with the commercial acaricide cyenopyrafen (LC₅₀ = 0.13 mg/L).</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 6","pages":"930 - 943"},"PeriodicalIF":2.6,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141120797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The emergence of sulfo-click amidation in kinetic target-guided synthesis","authors":"Prakash T. Parvatkar, Roman Manetsch","doi":"10.1007/s00044-024-03236-w","DOIUrl":"https://doi.org/10.1007/s00044-024-03236-w","url":null,"abstract":"<p>Sulfo-click is a chemoselective and biocompatible reaction between thioacids and sulfonyl azides that forms highly versatile <i>N</i>-acylsulfonamides, interesting bioisosteres of carboxylic acids. This reaction is useful for chemists and biologists and has many applications in medicinal chemistry, drug discovery, bioconjugation chemistry, and chemical biology. Sulfo-click amidations have been extensively used in kinetic target-guided synthesis (KTGS) to identify modulators of protein-protein interactions (PPIs). Different variants of KTGS screening, such as binary and multi-fragments, as well as one-pot deprotection/amidation strategies, have been successfully performed using sulfo-click chemistry. In this mini-review, we discuss the recent developments of sulfo-click amidation in KTGS and provide directions for future research.</p>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"47 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141060321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of semisynthetic saponin immunostimulants","authors":"Di Bai, Hyunjung Kim, Pengfei Wang","doi":"10.1007/s00044-024-03227-x","DOIUrl":"https://doi.org/10.1007/s00044-024-03227-x","url":null,"abstract":"<p>Many natural saponins demonstrate immunostimulatory adjuvant activities, but they also have some inherent drawbacks that limit their clinical use. To overcome these limitations, extensive structure-activity-relationship (SAR) studies have been conducted. The SAR studies of QS-21 and related saponins reveal that their respective fatty side chains are crucial for potentiating a strong cellular immune response. Replacing the hydrolytically unstable ester side chain in the C28 oligosaccharide domain with an amide side chain in the same domain or in the C3 branched trisaccharide domain is a viable approach for generating robust semisynthetic saponin immunostimulants. Given the striking resemblance of natural <i>momordica</i> saponins (MS) I and II to the deacylated <i>Quillaja Saponaria</i> (QS) saponins (e.g., QS-17, QS-18, and QS-21), incorporating an amide side chain into the more sustainable MS, instead of deacylated QS saponins, led to the discovery of MS-derived semisynthetic immunostimulatory adjuvants VSA-1 and VSA-2. This review focuses on the authors’ previous work on SAR studies of QS and MS saponins.</p>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"27 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141060340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A very promising antibiofilm activity against Candida albicans from an in vitro screening for antimicrobial, antibiofilm and antiproliferative activity of new synthesized 4-cinnamamido- and 2-phenoxyacedamido-1H-pyrazol-5-yl)benzamides","authors":"Fabiana Plescia,&nbsp;Valentina Catania,&nbsp;Antonella D’Anneo,&nbsp;Demetrio Raffa,&nbsp;Marianna Lauricella,&nbsp;Domenico Schillaci","doi":"10.1007/s00044-024-03224-0","DOIUrl":"10.1007/s00044-024-03224-0","url":null,"abstract":"<div><p>Several new synthesized 4-cinnamamido- and 2-phenoxyacedamido-(1H-pyrazol-5-yl)benzamides were obtained by two multi step different synthetic routes in order to maximize their yield. The new derivatives were screened to determine the antiproliferative, antimicrobial and antibiofilm activity. The biological results showed how, respect to the antiproliferative and antimicrobial activities, the compounds have a low to missing activity. Different are the results obtained concerning the antibiofilm activity, especially towards <i>Candida albicans</i>. Most of the synthesized compounds showed a good percentage inhibition of biofilm formation ranging from 60 to 73% with a Biofilm Inhibition Concentration 50% (BIC₅₀) from 0.13 to 0.01 µM. Among the synthesized compounds the ethyl 5-(4-(2-(4-chlorophenoxy)acetamido)benzamido)-1-methyl-1H-pyrazole-4-carboxylate (<b>27c</b>) resulted the most active molecule with a BIC₅₀ of 0.01 µM. According to the results obtained, such compound could be considered a lead subject of further studies to obtain novel and more effective antibiofilm agents against <i>C. albicans</i>.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 6","pages":"903 - 917"},"PeriodicalIF":2.6,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-024-03224-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140975680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Candida albicans ergosterol disorders as a consequence of the new sulfone derivative action mode","authors":"Monika Staniszewska,&nbsp;Michalina Kazek,&nbsp;Marta Rogalska,&nbsp;Anna Wojewódzka,&nbsp;Łukasz Kuryk,&nbsp;Zbigniew Ochal","doi":"10.1007/s00044-024-03234-y","DOIUrl":"10.1007/s00044-024-03234-y","url":null,"abstract":"<div><p>A series of novel sulfone derivatives were synthesized and screened in vitro for their cytotoxicity and antifungal activity with annotated primary mechanism of action (MOA). We prioritized sulfones with high (4-(bromodichloromethylsulfonyl)benzoic acid <b>4</b>, 4-(difluoromethylsulfonyl)benzoic acid <b>12</b>), little (3-[4-(bromodichloromethylsulfonyl)phenyl]propanoic acid <b>8</b>, difluoromethyl 4-methylphenyl sulfone <b>11</b>, 4-(difluoromethylsulfonyl)benzoic acid <b>12</b>), or no cytotoxicity of 4-(4-(dichloromethylsulfonyl)benzoic acid <b>3)</b> and 3-[4-(dichloromethylsulfonyl)phenyl]propanoic acid <b>7</b> against mammalian cell lines. <b>3</b> was found to be the most potent sulfone against <i>Candida albicans</i> (R_log=7.25 at 128–256 µg/mL). The mutation in the <i>CNB1</i> gene (1) increased the sensitivity of the <i>C. albicans</i> biofilm to <b>3</b>; (2) reduced ergosterol production and therefore generated higher susceptibility to <b>4</b>. Sulfone <b>4</b> at 128 µg/mL increased cellular RH-123 fluorescence in the wild-type cells of <i>C. albicans</i>, except <i>CNB1/cnb1∆</i>. Moreover, the uptake of sulfones into the cell was unaffected regardless of the presence or absence of RH-123, and the uptake of sulfones was strictly cell/strain dependent. Both RH123 and sulfones cumulatively competed with one another for access to transporters. Calcineurin played a role in this mechanism.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 6","pages":"964 - 976"},"PeriodicalIF":2.6,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-024-03234-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140979956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Naturally occurring and artificially designed antimicrobial peptides: a comparative study of Mastoparan C and BP52","authors":"Hai Bui Thi Phuong,&nbsp;Yen Do Hai,&nbsp;Viet Nguyen Huu,&nbsp;Anh Luong The,&nbsp;Minh Nguyen Hong,&nbsp;Huy Luong Xuan","doi":"10.1007/s00044-024-03205-3","DOIUrl":"10.1007/s00044-024-03205-3","url":null,"abstract":"<div><p>Antimicrobial peptides (AMPs) are naturally occurring molecules that play a vital role in the innate immune responses of various organisms. Additionally, artificial AMPs are also designed based on the common structure-activity relationships (SARs) found in natural ones. As part of our ongoing effort to explore the advantages of each source, this study focused on two representative helical AMPs: Mastoparan C (MPC) and BP52. While the former is derived from the venom of the European wasp <i>Vespa crabro</i>, the latter belongs to a group of artificially designed AMPs inspired by the structure of two natural peptides, Cecropin A and Melittin M. Our data suggests that BP52 exhibits similar antimicrobial activity to MPC but demonstrates significantly higher potency against the A427 cancer cells. Taken together with the shorter length and reduced toxicity to human red blood cells, BP52 exhibited greater potential in drug development compared to its counterpart MPC, thus highlighting the potential of rational design in developing short, potent and selective membrane-active peptides.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 5","pages":"735 - 739"},"PeriodicalIF":2.6,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140931011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent pharmacological insights about imidazole hybrids: a comprehensive review","authors":"Samet Poyraz,&nbsp;Metin Yıldırım,&nbsp;Mehmet Ersatir","doi":"10.1007/s00044-024-03230-2","DOIUrl":"10.1007/s00044-024-03230-2","url":null,"abstract":"<div><p>In this review, we evaluated the biological activities of hybrid molecules incorporating imidazoles—a cornerstone in medicinal chemistry known for their broad pharmacological spectrum, attributed to the chemical characteristics of their nitrogen atoms. In contrast to earlier reviews, which have concentrated their attention only on a single biological activity that is connected with these hybrid molecules, this review brings together the findings of a variety of investigations that cover a wide range of significant activities including antibacterial, antifungal, antituberculosis, antiviral, anticancer, antioxidant, antidiabetic, anti-inflammatory, and analgesic effects, along with the inhibition of cholinesterase, carbonic anhydrase, and monoamine oxidase (MAO) enzymes. Furthermore, we examined significant pharmacophores such as triazole, thiazole, indole, pyrazole, quinoline, sulfonamide, pyridine, chalcone, coumarin, pyrrole, and pyrrolidine, integrated into imidazole hybrids. Molecular docking studies and structure-activity relationship (SAR) discussions provide insight into the interactions of imidazole hybrids with key enzymes and receptors. This work aspires to contribute valuable insights into the development of novel imidazole hybrids, aiming to address critical health challenges of our era.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 6","pages":"839 - 868"},"PeriodicalIF":2.6,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140930978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis of novel benzothieno-[3,2’-f][1,3] oxazepines and their isomeric 2-oxo-2H-spiro[benzothiophene-3,3’-pyrrolines] via 1,4-dipolar cycloaddition reaction and their evaluation as cytotoxic anticancer leads","authors":"Mohammed M. Al-Mahadeen,&nbsp;Areej M. Jaber,&nbsp;Jalal A. Zahra,&nbsp;Mustafa M. El-Abadelah,&nbsp;Walhan Alshaer,&nbsp;Mutasem O. Taha","doi":"10.1007/s00044-024-03229-9","DOIUrl":"10.1007/s00044-024-03229-9","url":null,"abstract":"<div><p>This study introduces a novel class of hybrid compounds, namely, benzothieno[3,2’-<i>f</i>][1,3]oxazepines and their isomeric 2-oxo-2<i>H</i>-spiro[benzothiophene-3,3’-pyrrolines]. The synthetic strategy employs a three-component reaction and 1,4-Dipolar cycloaddition, yielding spiro and oxazepine compounds. Structural elucidation <i>via</i> NMR and MS analyses is complemented by X-ray crystallography and a proposed mechanistic pathway. Biological evaluation against HEK-293 and HT-29 cells reveals potent and selective cytotoxicity against HEK-293 without cytotoxic effects against HT-29 cells. Compound <b>16c</b> exhibited the highest cytotoxic properties with IC₅₀ = 4.30 μM against HEK-293 cells. Accordingly, the new compounds can be considered as promising leads for possible optimization into novel selective cytotoxic treatments.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 6","pages":"918 - 929"},"PeriodicalIF":2.6,"publicationDate":"2024-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140930975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}