Archiv der Pharmazie最新文献

{"title":"Symmetrical 2,7-disubstituted 9H-fluoren-9-one as a novel and promising scaffold for selective targeting of SIRT2","authors":"Selen Gozde Kaya,&nbsp;Gokcen Eren,&nbsp;Alberto Massarotti,&nbsp;Habibe Beyza Gunindi,&nbsp;Filiz Bakar-Ates,&nbsp;Erva Ozkan","doi":"10.1002/ardp.202400661","DOIUrl":"10.1002/ardp.202400661","url":null,"abstract":"<p>Sirtuin 2 (SIRT2) belongs to the family of silent information regulators (sirtuins), which comprises nicotinamide adenine dinucleotide (NAD⁺)-dependent protein lysine deacetylases. With a distribution across numerous tissues and organs of the human body, SIRT2 is involved in a wide range of physiological and pathological processes, such as regulating the cell cycle, energy metabolism, DNA repair, and tumorigenesis. Aberrant expression of SIRT2 has been closely associated with particular etiologies of human diseases, positioning SIRT2 as a promising therapeutic target. Herein, we detail the design overview and findings of novel symmetrical 2,7-disubstituted 9<i>H</i>-fluoren-9-one derivatives targeting SIRT2. <b>SG3</b> displayed the most potent SIRT2-selective inhibitory profile, with an IC₅₀ value of 1.95 <span></span><math>\u0000 <semantics>\u0000 <mrow>\u0000 <mi>μ</mi>\u0000 \u0000 <mi>M</mi>\u0000 </mrow>\u0000 </semantics></math>, and reduced the cell viability of human breast cancer MCF-7 cells accompanied by hyperacetylation of α-tubulin. Finally, molecular docking, molecular dynamics simulations, and binding free energy calculations using molecular mechanics/generalized born surface area method were performed to verify the binding ability of <b>SG3</b> to SIRT2. Taken together, these results could enhance our understanding of the structural elements necessary for inhibiting SIRT2 and shed light on the mechanism of inhibition.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"357 12","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.202400661","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel benzothiazole/benzothiazole thiazolidine-2,4-dione derivatives as potential FOXM1 inhibitors: In silico, synthesis, and in vitro studies","authors":"Khaled A. N. Abusharkh,&nbsp;Ferah Comert Onder,&nbsp;Venhar Çınar,&nbsp;Alper Onder,&nbsp;Merve Sıkık,&nbsp;Zuhal Hamurcu,&nbsp;Bulent Ozpolat,&nbsp;Mehmet Ay","doi":"10.1002/ardp.202400504","DOIUrl":"10.1002/ardp.202400504","url":null,"abstract":"<p>The oncogenic transcription factor FOXM1 overexpressed in breast and other solid cancers, is a key driver of tumor growth and progression through complex interactions, making it an attractive molecular target for the development of targeted therapies. Despite the availability of small-molecule inhibitors, their limited specificity, potency, and efficacy hinder clinical translation. To identify effective FOXM1 inhibitors, we synthesized novel benzothiazole derivatives (<b>KC10–KC13</b>) and benzothiazole hybrids with thiazolidine-2,4-dione (<b>KC21–KC36</b>). These compounds were evaluated for FOXM1 inhibition. Molecular docking and molecular dynamics simulation analysis revealed their binding patterns and affinities for the FOXM1-DNA binding domain. The interactions with key amino acids such as Asn283, His287, and Arg286, crucial for FOXM1 inhibition, have been determined with the synthesized compounds. Additionally, the molecular modeling study indicated that <b>KC12</b>, <b>KC21</b>, and <b>KC30</b> aligned structurally and interacted similarly to the reference compound FDI-6. In vitro studies with the MDA-MB-231 breast cancer cell line demonstrated that <b>KC12</b>, <b>KC21</b>, and <b>KC30</b> significantly inhibited FOXM1, showing greater potency than FDI-6, with IC₅₀ values of 6.13, 10.77, and 12.86 µM, respectively, versus 20.79 µM for FDI-6. Our findings suggest that <b>KC12</b>, <b>KC21</b>, and <b>KC30</b> exhibit strong activity as FOXM1 inhibitors and may be suitable for in vivo animal studies.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"357 12","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.202400504","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"iNOS/PGE2 inhibitors as a novel template for analgesic/anti-inflammatory activity: Design, synthesis, in vitro biological activity and docking studies","authors":"Ayca Erdogan,&nbsp;Yagmur Ozhan,&nbsp;Hande Sipahi,&nbsp;Enise Ece Gurdal,&nbsp;Wolfgang Sippl,&nbsp;Meric Koksal","doi":"10.1002/ardp.202400238","DOIUrl":"10.1002/ardp.202400238","url":null,"abstract":"<p>Due to the serious gastrointestinal side effects associated with prolonged use of current anti-inflammatory therapies, various strategies such as the regulation of nitric oxide (NO) and prostaglandin E₂ (PGE₂) production have been explored in the field of anti-inflammatory drug development. In this study, a series of disubstituted 1,3,4-oxadiazoles (<b>3a–f</b> and <b>4a–f</b>) and their cyclized 1,2,4-triazole derivatives (<b>5a–e</b> and <b>6a–e</b>) were synthesized and tested for their NO, PGE₂, and interleukin-6 (IL-6) releasing inhibition ability. All of the compounds were observed to reduce lipopolysaccharide (LPS)-induced nitrite production in a concentration-dependent manner. Moreover, compounds <b>3b</b> (50 μM) and <b>6d</b> (1 μM) exhibited 63% and 49% inhibition, respectively, while indomethacin showed 52% at 100 μM. Based on a preliminary NO inhibition assay, 10 of the compounds (<b>3a</b>, <b>3b</b>, <b>3e</b>, <b>4b</b>, <b>4d</b>, <b>6a–e</b>) were selected to be evaluated for in vitro PGE₂, IL-6, and inducible nitric oxide synthase (iNOS) inhibition. Notably, compound <b>6d</b> proved to be the most active of the series with the lowest dose (1 µM), in comparison to the other further tested compounds (5–100 µM) and the reference drug indomethacin (100 µM). The inhibitory activity of the compounds was supported by docking simulations into the binding site of the iNOS protein receptor (Protein Data Bank [PDB]ID: 3E7G). The data showing that <b>4d</b> reduced iNOS levels the most can be explained by the H-bond with Tyr347 through oxadiazole and π–halogen interactions through the <i>p</i>-bromo, in addition to aromatic interactions with protoporphyrin IX.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"357 12","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.202400238","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142277499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, evaluation, pharmacophore modeling, and 3D-QSAR of lappaconitine analogs as potential analgesic agents","authors":"Jingchuan Wu,&nbsp;Xiaohong Lai,&nbsp;Yinyong Zhang,&nbsp;Yuzhu Li,&nbsp;Shuai Huang,&nbsp;Lin Chen,&nbsp;Xianli Zhou","doi":"10.1002/ardp.202400528","DOIUrl":"10.1002/ardp.202400528","url":null,"abstract":"<p>Alleviating pain is crucial for patients with various diseases. This study aimed to enhance the analgesic properties of lappaconitine, a natural drug, through structural modifications. Specifically, carbamate analgesic active fragments were innovatively introduced at multiple sites on the benzene ring of lappaconitine. A total of 53 lappaconitine analogs were synthesized and evaluated. Compounds <b>5a</b>, <b>5c</b>, <b>5e</b>, <b>6</b>, and <b>15j</b> addressed the narrow therapeutic window of lappaconitine, enhancing drug safety. Notably, carbamate analogs exhibited significantly enhanced analgesic activity, with compounds <b>5a</b> and <b>5c</b> having ED₅₀ values of 1.2 and 1.6 mg/kg, respectively, indicating higher potency than lappaconitine (3.5 mg/kg). A metabolic analysis of compound <b>5e</b> was conducted in mice, revealing its primary metabolic processes and metabolites, and providing preliminary exploration for the druggability. Given the multiple analgesic targets of lappaconitine, its analgesic mechanism remains inconclusive. This study, for the first time, analyzed the pharmacological activity characteristics of the lappaconitine analogs using a pharmacophore model and established a three-dimensional quantitative structure–activity relationship (3D-QSAR) to elucidate the quantitative relationship between the structures of the synthesized compounds and their analgesic activities. These findings provide valuable guidance for future structural modification and optimization of analgesic drugs.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"357 12","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142257247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of new pyrazoles as class I HDAC inhibitors: Synthesis, molecular modeling, and biological characterization in leukemia cells","authors":"Francesco Berluti,&nbsp;Fady Baselious,&nbsp;Sven Hagemann,&nbsp;Sebastian Hilscher,&nbsp;Matthias Schmidt,&nbsp;Stefan Hüttelmaier,&nbsp;Mike Schutkowski,&nbsp;Wolfgang Sippl,&nbsp;Hany S. Ibrahim","doi":"10.1002/ardp.202400437","DOIUrl":"10.1002/ardp.202400437","url":null,"abstract":"<p>Class I histone deacetylases (HDACs) are considered promising targets in current cancer research. To obtain subtype-selective and potent HDAC inhibitors, we used the aminobenzamide scaffold as the zinc-binding group and prepared new derivatives with a pyrazole ring as the linking group. The synthesized compounds were analyzed in vitro using an enzymatic assay against HDAC1, −2, and −3. Compounds <b>12b</b>, <b>15b</b>, and <b>15i</b> were found to be potent HDAC1 inhibitors, also in comparison to the reference compounds entinostat and tacedinaline, with IC₅₀ values of 0.93, 0.22, and 0.68 μM, respectively. The best compounds were measured for their cellular effect and target engagement in acute myeloid leukemia (AML) cells. In addition, we studied the interaction of the compounds with HDAC subtypes using docking and molecular dynamic simulations. In summary, we have developed a new chemotype of HDAC1 inhibitors that can be used for further structure-based optimization.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"357 11","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.202400437","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142257248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EGB761 ameliorates mild cognitive impairment by inhibiting the pyroptosis and apoptosis in both in vivo and in vitro experiments","authors":"Xiaolu Zhang,&nbsp;Yingxin Sun,&nbsp;Yujia Zheng,&nbsp;Ruifeng Zhang,&nbsp;Xu Yan,&nbsp;Huayuan Wei,&nbsp;Lin Yang,&nbsp;Xijuan Jiang","doi":"10.1002/ardp.202400593","DOIUrl":"10.1002/ardp.202400593","url":null,"abstract":"<p>Mild cognitive impairment (MCI) is a neurodegenerative condition that is clinically prevalent among the elderly. EGB761 is widely recognized for its promising therapeutic properties in both the prevention and treatment of neurodegenerative disorders. The aim of this study was to investigate the effects of EGB761 in MCI and the underlying molecular mechanism. Four-month-old SAMP8 mice were used as an in vivo MCI model, and BV2 microglial cells were treated with β-amyloid (Aβ) 1–42 to establish an in vitro model. First, the cognitive function was evaluated by the Morris water maze. Then, Aβ levels were measured by enzyme-linked immunosorbent assay. Finally, the underlying molecular mechanism was investigated both in vivo and in vitro. It was found that EGB761 treatment improved the cognitive impairment of SAMP8 mice. In addition, EGB761 inhibited NOD-like receptor protein 3 inflammasome-mediated pyroptosis-related mRNAs and proteins and reduced pyroptosis markers, including gasdermin D fluorescence intensity, propidium iodide-positive cell count, and the lactate dehydrogenase content. Furthermore, EGB761 inhibited extrinsic and intrinsic apoptosis. Thus, EGB761 had protective effects against pyroptosis and apoptosis in BV2 microglial cells induced by Aβ1-42 and SAMP8 mice.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"357 11","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142257250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multispectral investigation of natural resins","authors":"Lara Heidrich,&nbsp;Bastian Brand,&nbsp;Stefan Brackmann,&nbsp;Jan Schäuble,&nbsp;Mohammed Adel Aly,&nbsp;Raphael Reher,&nbsp;Tanja Pommerening,&nbsp;Martin Koch","doi":"10.1002/ardp.202400517","DOIUrl":"10.1002/ardp.202400517","url":null,"abstract":"<p>Resins have been used as remedies since ancient times and various embalming resins have been identified in recent years. In Europe, <i>Mumia vera aegyptiaca</i>, a resinous substance from ancient Egyptian mummies, was even sold in pharmacies as a tonic until the early 20th century. It is difficult to examine the composition of these archeological samples in detail as the well-established analytical techniques, that is, gas chromatography-mass spectrometry or liquid chromatography coupled with tandem mass spectrometry, are destructive and therefore do not allow the analysis of valuable archeological samples. Hence, there is an urgent need for alternative, nondestructive methods for the identification of resin residues. This study aims to explore and compare the use of five spectroscopic methods as an alternative to established analytical procedures. For that, 15 resin samples of known origin and three samples from an Egyptian market were studied. While laser induced-breakdown spectroscopy and terahertz time-domain spectroscopy provide only limited information for resin classification, nuclear magnetic resonance spectroscopy and Fourier-transform infrared spectroscopy can be used to classify the resin samples more accurately. Furthermore, photoluminescence/photoluminescence excitation spectroscopy shows a promising potential in combination with its general advantages, such as cost-efficiency, nondestructive nature, and fast data acquisition.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"357 11","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.202400517","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142257249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vitro assessment of skin permeation properties of enzymatically derived oil-based fatty acid esters of vitamin C","authors":"Marija Ćorović,&nbsp;Milica Veljković,&nbsp;Ana Milivojević,&nbsp;Anja P. Ivanković,&nbsp;Stevan Blagojević,&nbsp;Rada Pjanović,&nbsp;Dejan Bezbradica","doi":"10.1002/ardp.202400538","DOIUrl":"10.1002/ardp.202400538","url":null,"abstract":"<p>Current topical formulations containing vitamin C face limitations in therapeutic effectiveness due to the skin's selective properties that impede drug deposition. Consequently, the widespread use of toxic and irritating chemical permeation enhancers is common. Hereby, we investigated enzymatically derived fatty acid ascorbyl esters (FAAEs) obtained using natural oils for their skin permeation properties using the Strat-M® skin model in a Franz cell diffusion study. By evaluating various cosmetic formulations without added enhancers, we found that emulgel is most suitable for enhancing the cutaneous and transdermal delivery of FAAEs. Furthermore, medium-chain coconut oil-derived FAAEs exhibited faster diffusion rates compared to sunflower oil-based FAAEs with long-side acyl residues, including the commonly applied ascorbyl palmitate. Experimental data were successfully fitted using the Peppas and Sahlin model, which accounted for a <i>lag</i> phase and the combined effect of Fickian diffusion and polymer relaxation. In the case of long-chain esters, the <i>lag</i> phase was prolonged, and the calculated effective diffusion coefficients (<i>D</i>_eff) were lower compared to medium-chain FAAEs. Accordingly, the highest <i>D</i>_eff value was observed for ascorbyl caprylate, being even 60 times higher than for ascorbyl palmitate. These results suggest the emerging potential of emulgel with incorporated coconut oil-derived FAAEs for efficiently delivering vitamin C into the skin.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"357 11","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142269483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New hydrazide derivatives of N-amino-11-azaartemisinin as promising epidermal growth factor receptor inhibitors for therapeutic development in triple-negative breast cancer","authors":"Manvika Karnatak,&nbsp;Priyanka Yadav,&nbsp;Komal Rathi,&nbsp;Monika Shukla,&nbsp;Prachi Dugam,&nbsp;Shruthi Suthakaran,&nbsp;Varun Rawat,&nbsp;Mohammad Hassam,&nbsp;Aditi Pandey,&nbsp;Ram Awatar Maurya,&nbsp;Debanjan Sen,&nbsp;Sudhan Debnath,&nbsp;Amitava Das,&nbsp;Achal Mukhija,&nbsp;Ved Prakash Verma","doi":"10.1002/ardp.202400466","DOIUrl":"10.1002/ardp.202400466","url":null,"abstract":"<p>Triple-negative breast cancer (TNBC) treatments, such as DNA-damaging agents like carboplatin, pose considerable human toxicity and may contribute to cancer relapse. Artemisinin derivatives offer a less toxic alternative; however, their specific role in TNBC management remains to be established. To address this gap, computational models were employed to design and evaluate artemisinin-based prototypes as potential TNBC therapeutics, aiming to provide safer and more effective treatment options for this aggressive cancer subtype. Among the series of hydrazide derivatives of azaartemisinin (<b>10a–l</b>) reported herein, compound <b>10j</b> emerged as the most promising, exhibiting notable cytotoxicity with IC₅₀ values of 1.74 and 1.64 µM against MDA-MB-231 and MDA-MB-468 cells, respectively. The clinically useful drug doxorubicin provided IC₅₀ values of 0.29 and 0.29 µM against MDA-MB-231 and MDA-MB-468 cells, while artemisinin provided IC₅₀ values of 107.30 and 116.60 µM, respectively. Furthermore, putative interactions between the synthesized compounds and the epidermal growth factor receptor (EGFR) were identified using molecular docking studies, suggesting a possible mechanism for their anticancer effect. Additionally, to determine the thermodynamic parameters of the interactions between artemisinin, azaartemisinin, and biomolecules, isothermal titration calorimetry experiments were performed. The binding constant value on the order of 10⁴ indicates a comparatively stronger binding affinity of azaartemisinin with human serum albumin (HSA) compared to artemisinin with HSA. These findings support the potential of azaartemisinin derivatives as promising EGFR inhibitors for therapeutic development in TNBC, offering a new avenue for less toxic and more effective cancer treatments.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"357 11","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142257251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repurposing antiparasitic N,N′-aliphatic diamine derivatives as promising antimycobacterial agents","authors":"Alejandro I. Recio-Balsells,&nbsp;Renzo Carlucci,&nbsp;Simone Giovannuzzi,&nbsp;Fabrizio Carta,&nbsp;Claudiu T. Supuran,&nbsp;Babu L. Tekwani,&nbsp;Héctor R. Morbidoni,&nbsp;Guillermo R. Labadie","doi":"10.1002/ardp.202400597","DOIUrl":"10.1002/ardp.202400597","url":null,"abstract":"<p>In previous studies, we demonstrated the potent activity of a library of 25 <i>N,N′</i>-disubstituted diamines (NNDDA) toward Trypanosomatid and Apicomplexa parasites. Considering the structure similarity between this collection and SQ109, an antituberculosis compound, and its compelling antiparasitic properties, we aimed to repurpose this library for tuberculosis treatment. We assayed this collection against <i>Mycobacterium tuberculosis</i> H37<i>Rv</i> and <i>M. avium</i>, obtaining several compounds with MIC values below 10 µM. The most active analogs were also evaluated against <i>M. smegmatis</i>, a non-pathogenic species, and the non-tuberculosis mycobacteria <i>M. abscessus</i>, <i>M. kansasii</i>, and <i>M. fortuitum</i>. <b>3c</b> stands out as the lead mycobacterial compound of the collection, with potent activity against <i>M. tuberculosis</i> (minimal inhibitory concentration [MIC] = 3.4 µM) and moderate activity against <i>M. smegmatis</i>, <i>M. kansasii</i>, and M<i>. fortuitum</i> (all with MIC values of 26.8 µM). To unravel the mechanism of action, we employed the web-based platform Polypharmacology Browser 2 (PPB2), obtaining carbonic anhydrases as potential drug targets. Nevertheless, none of the compounds displayed experimental inhibition. In summary, our study confirms the validity of the repurposing approach and underscores the antimycobacterial potential of NNDDA compounds, especially the analog <b>3c</b>, setting a stepping stone for further studies.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"357 11","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142218851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}