Bioorganic Chemistry最新文献

{"title":"Synthesis and biological evaluation of 4-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)quinoline derivatives as novel potential transforming growth factor-β type 1 receptor inhibitors for hepatocellular carcinoma","authors":"Siyuan Liu ,&nbsp;Fusheng Wang ,&nbsp;Caifang Zhang ,&nbsp;Hong Jiang ,&nbsp;Chun Liu","doi":"10.1016/j.bioorg.2025.108156","DOIUrl":"10.1016/j.bioorg.2025.108156","url":null,"abstract":"<div><div>The transforming growth factor β (TGF-β) type 1 receptor (ALK5) plays a key role in tumor microenvironment. Small-molecule inhibitors of TGFβR1 provides a prospective approach for the treatment of malignant tumors. In this study, a series of 4-((3-(tetrahydro-2<em>H</em>-pyran-4-yl)-1<em>H</em>-pyrazol-4-yl)oxy)quinoline derivatives were identified as novel, potential TGFβR1 inhibitors. The most potent compound <strong>16w</strong> inhibited SMAD2/3 phosphorylation and H22 cell viability with IC₅₀ values of 12 and 65 nM, respectively. Further, compound <strong>16w</strong> exhibited reasonable pharmacokinetic profiles and exhibited significant anti-tumor efficacy in a xenograft model of H22 cells, with TGI of 79.6 %. Additionally, compound <strong>16w</strong> also showed a strong synergistic proapoptotic effect in combination with sorafenib, which provided a promising lead for further development of novel anticancer drugs.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108156"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring 1,2,3-triazole-Schiff’s base hybrids as innovative EGFR inhibitors for the treatment of breast cancer: In vitro and in silico study","authors":"Nareman A. Nawareg ,&nbsp;Asmaa S.A. Yassen ,&nbsp;Ebtehal M. Husseiny ,&nbsp;Magda A.A. El-Sayed ,&nbsp;Hosam A. Elshihawy","doi":"10.1016/j.bioorg.2024.108106","DOIUrl":"10.1016/j.bioorg.2024.108106","url":null,"abstract":"<div><div>EGFR inhibitors are a class of targeted therapies utilized in the management of certain tumor kinds such as NSCLC and breast cancer. Series of 1,2,3-triazole-Schiff’s base hybrids were designed, synthesized, and estimated for their antitumor effect toward breast cancer cells, MCF-7 and MDA-MB-231. The safety and selectivity of the new compounds were tested using normal cell (WI-38). Analogs <strong>4a</strong>, <strong>4b,</strong> and <strong>5f</strong> demonstrated significant antitumor effects toward both MCF-7 and MDA-MB-231 with IC₅₀ range of 5.61–18.01 µM in comparison to Doxorubicin (6.72 µM). Moreover, they proved considerable selectivity toward the tested cancer cells (SI values of 4.36–5.33). The superior compounds were investigated for EGFR inhibition where compounds <strong>4b</strong> and <strong>5f</strong> showed the highest EGFR inhibition effect with IC₅₀ equal 0.16 and 0.15 µM, respectively utilizing Gefitinib as reference (IC₅₀ = 0.081 µM). Further mechanistic studies for hybrid <strong>5f</strong> in MDA-MB-231 cells, exhibited cell cycle arrest at G2/M phase by 29.85 % that was accompanied by the elevation of apoptosis percent by 48-fold more than the control. The apoptosis studies indicated that hybrid <strong>5f</strong> was able to upregulate Bax (9.43 folds) while downregulate Bcl-2 (0.27) with substantial remarkable elevation of Bax/Bcl-2 ratio (35:1). Furthermore, it upregulated both caspases 8 and 9 by 2.93 and 6.54-fold, respectively. Molecular modeling studies showed the good binding affinity of compounds <strong>4b</strong> and <strong>5f</strong> with EGFR kinase active site explaining their potent biological effects. Drug likeness and ADMET features of compounds <strong>4b</strong> and <strong>5f</strong> demonstrated that they represent promising drug like candidates against breast cancer.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108106"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calliloboapins A-L, diterpenoids from the branches and leaves of Callicarpa loboapiculata and their biological activities","authors":"Ting Liu ,&nbsp;Xiao-Lu Wu ,&nbsp;Yu-Xia Fu,&nbsp;Tao Ding,&nbsp;De-Sheng Ning,&nbsp;Zheng-Hong Pan","doi":"10.1016/j.bioorg.2025.108234","DOIUrl":"10.1016/j.bioorg.2025.108234","url":null,"abstract":"<div><div>Eleven new isopimarane diterpenoids and one new <em>ent</em>-pimarane diterpenoid, named calliloboapins A-L (<strong>1</strong>–<strong>12</strong>), were isolated from the branches and leaves of <em>Callicarpa loboapiculata</em> F. P. Metcalf. Their structures and absolute configurations were established by HRESIMS, UV, IR, 1D and 2D NMR spectroscopic analyses, single crystals X-ray diffraction and ECD calculations. Structurally, compound <strong>1</strong> possesses an unusual tricyclo [2.2.2.0] octane structure, and compound <strong>2</strong> is characterized by a cyclopentane ring B. Compound <strong>3</strong> contains an unprecedented ten-membered ring with an oxygen bridge connecting C-8 and C-9. The anti-inflammatory activities of all isolated compounds were evaluated by LPS-induced RAW264.7 cells. Compounds <strong>1</strong>–<strong>12</strong> inhibited the release of NO to varying degrees, and <strong>3</strong>, <strong>4</strong>, <strong>8</strong>, <strong>11</strong> and <strong>12</strong> significantly suppressed the overexpression of inducible NO synthase. Moreover, liver X receptor alpha (LXRα) was predicted to be the probable target of isolates by Swiss Target Prediction tool, and compounds <strong>2</strong>–<strong>4</strong>, <strong>11</strong> and <strong>12</strong> increased the protein expression of ATP-binding cassette transporter (ABCA1), showing potential antiatherogenic properties.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"156 ","pages":"Article 108234"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143197026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical pharmacokinetics, absolute bioavailability and dose proportionality evaluation of bioactive phytochemical Withanone in rats","authors":"Sandeep K. Singh ,&nbsp;Mamunur Rashid ,&nbsp;Swati Chaturvedi ,&nbsp;Arun Agarwal ,&nbsp;Divya Chauhan ,&nbsp;Jiaur R. Gayen ,&nbsp;Muhammad Wahajuddin","doi":"10.1016/j.bioorg.2025.108128","DOIUrl":"10.1016/j.bioorg.2025.108128","url":null,"abstract":"<div><div>Withanone (WN), a bioactive phytochemical isolated from the medicinal herb <em>Withania somnifera</em>, has shown multiple pharmacological and therapeutic successes, including neuroprotective and anti-cancer activities. However, detailed pharmacokinetic (PK) properties of pure WN were not well defined. Pharmacokinetic (PK) characteristics, dose proportionality, and absolute bioavailability of pure WN were explored in rats using an efficient, reliable, and sensitive LC-MS/MS assay to address this gap. The method shows excellent linearity over 0.5–500 ng/mL (r² ≥ 0.99), is accurate, and requires less analysis time. A dose proportionality and absolute bioavailability of pure WN were determined in <em>Sprague-Dawley</em> (<em>SD</em>) rats through three ascending oral (10, 20, and 40 mg/kg) and single intravenous (5 mg/kg) PK studies. The peak concentration (Cmax) of WN was 60.53 ± 20.33, 116.30 ± 16.89, and 91.62 ± 6.20 ng/mL, corresponding to oral dosage of 10, 20, and 40 mg/kg, respectively. WN shows poor systemic exposure upon oral administration, leading to low oral bioavailability (&lt;15 %). Additionally, the dose proportionality studies of WN revealed its saturable bioavailability and non-proportional systemic exposure over the dosage range of 10–40 mg/kg in rats. The obtained PK findings of this study would be valuable for better understanding the pharmacological effects of WN, dose regimen optimization for future studies, and relevance for clinical reference to support its future development as a potential therapeutic molecule.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108128"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142963339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 and in vivo Investigations of 4-Substituted 2-Phenylquinazoline derivatives as multipotent ligands for the treatment of Alzheimer’s disease","authors":"Vijay Kumar ,&nbsp;Kailash Jangid ,&nbsp;Vishal Kumar ,&nbsp;Naveen Kumar ,&nbsp;Jayapriya Mishra ,&nbsp;Tania Arora ,&nbsp;Ashish Ranjan Dwivedi ,&nbsp;Puneet Kumar ,&nbsp;Jasvinder Singh Bhatti ,&nbsp;Jyoti Parkash ,&nbsp;Vinod Kumar","doi":"10.1016/j.bioorg.2025.108126","DOIUrl":"10.1016/j.bioorg.2025.108126","url":null,"abstract":"<div><div>The pathology of Alzheimer’s disease (AD) is complex due to its multifactorial nature and single targeting drugs proved inefficient. A series of novel 4-<em>N</em>-substituted-2-phenylquinazoline derivatives was designed and synthesized as potential multi-target directed ligands (MTDLs) through dual inhibition of AChE and MAO-B enzymes along with Aβ₄₂ aggregation inhibition for the treatment of AD. Two compounds in the series, <strong>VAV-8</strong> and <strong>VAV-19</strong> were found to be the most potent inhibitors of both AChE and MAO-B enzymes and moderate inhibitor of Aβ₄₂, with good thermodynamic stability at the binding pocket of the enzymes. Both the ligands showed moderate ROS inhibition and neuroprotection potential and found to be permeable to the blood–brain barrier. Furthermore, <strong>VAV-8</strong> was subjected to toxicity evaluation and <em>in vivo</em> investigation using a zebrafish model. In adult zebrafish, <strong>VAV-8</strong> (5 μM, and 10 μM) was found to be effective in reducing cognitive deterioration, neurodegeneration, and oxidative stress induced by scopolamine. Thus, these quinazoline derivatives have the potential to be developed as MTDLs for the treatment of Alzheimer’s disease.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108126"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"pH-sensitive phthalocyanine-loaded polymeric nanoparticles as a novel treatment strategy for breast cancer","authors":"Katarzyna Malarz ,&nbsp;Wioleta Borzęcka ,&nbsp;Patryk Ziola ,&nbsp;Adrian Domiński ,&nbsp;Patrycja Rawicka ,&nbsp;Katarzyna Bialik-Wąs ,&nbsp;Piotr Kurcok ,&nbsp;Tomas Torres ,&nbsp;Anna Mrozek-Wilczkiewicz","doi":"10.1016/j.bioorg.2025.108127","DOIUrl":"10.1016/j.bioorg.2025.108127","url":null,"abstract":"<div><div>Novel pH-sensitive polymeric photosensitizer carriers from the phthalocyanine (<em>Pc</em>) group were investigated as potential photodynamic therapy drugs for the treatment of breast cancer. Their high antiproliferative activity was confirmed by photocytotoxicity studies, which indicated their high efficacy and specificity toward the SK-BR-3 cell line. Importantly, the Pcs encapsulated in the polymeric nanoparticle (NP) carrier exhibited a much better penetration into the acidic environment of tumor cells than their free form. The investigated Pc4-NPs and TT1-NPs exhibited a high selectivity to healthy fibroblasts as well as non-toxicity without irradiation. This paper describes the detailed mechanism of action of the evaluated compounds by measuring reactive oxygen species (ROS), including singlet oxygen; imaging cellular localization; and analyzing key signaling pathway proteins. An additional advantage of the evaluated compounds is their ability to inhibit the Akt protein expression, including its phosphorylation, which the Western blot test confirmed. This is particularly important because breast cancers often overexpress the HER-2 receptor-related signaling proteins. Moreover, an analysis of proteins such as GLUT-1, HO-1, phospho-p42/44, and BID revealed the significant involvement of ROS in disrupting cellular homeostasis, thereby leading to the induction of oxidative stress and resulting in apoptotic cell death.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108127"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis of tetra-substituted thiophene derivatives as potential Hits combating antibiotic resistant bacteria ESKAPE","authors":"Heba K. Abd El-Mawgoud ,&nbsp;Asmaa M. AboulMagd ,&nbsp;Ahmed M.M. Shaker ,&nbsp;Magdy M. Hemdan ,&nbsp;Aya I. Hassaballah ,&nbsp;Paula S. Farag","doi":"10.1016/j.bioorg.2024.108101","DOIUrl":"10.1016/j.bioorg.2024.108101","url":null,"abstract":"<div><div>The escalating prevalence of antibiotic-resistant bacteria has led to a serious global public health problem; therefore, there is an urgent need for the development of structurally innovative antibacterial agents. In our study, different series of tetra-substituted thiophene derivatives were designed and synthesized by multi-component reactions (MCRs) in moderate to excellent yields. Some of the designed final compounds were synthesized by both microwave assisted method and traditional synthesis. Thirteen compounds were evaluated against antibiotic resistance bacteria ESKAPE, among which compounds <strong>11</strong>, <strong>13</strong> and <strong>17</strong> showed the most potent inhibitory activities against multidrug-resistant <em>Enterococcus faecalis</em> with MIC (minimum inhibitory concentration) values as low as 15.62, 7.61 and 15.62 µg/mL, respectively. Two potent candidates <strong>11</strong> and <strong>13</strong> not only showed rapid bactericidal properties and impeded <em>E. faecalis</em> biofilm formation to effectually relieve the development of drug resistance, but also performed low toxicity toward human normal cells. Moreover, time dependent killing assay was performed that showed the reduction of the concentration of bacteria by 5.0 Log (CFU/mL) within 6 h, stronger than reference drug, ampicillin at the same concentration. Additionally, mechanistic investigation demonstrated that both compounds <strong>11</strong> and <strong>13</strong> could exert inhibitory activity against DHPS with IC₅₀ value of 1.73 and 4.67 µM, respectively and against DNA gyrase enzyme with IC₅₀ value of 0.07 and 0.04 µM, respectively. Moreover, the cytotoxic activity of the most active compound was crucial to be determined that showed IC₅₀ value of 75.42 µM. Molecular docking indicated that the binding of both compounds <strong>11</strong> and <strong>13</strong> to DHPS and DNA gyrase enzymes could hinder their function. These results can provide novel structures of antibacterial drugs chemically different from currently known antibiotics and broaden prospects for the development of effective antibiotics against antibiotic-resistant bacteria.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108101"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of mitoxantrone as a potent inhibitor of CDK7/Cyclin H via structure-based virtual screening and In-Vitro validation by ADP-Glo kinase assay","authors":"Tejaswi Somarowthu ,&nbsp;Rohan R. Patekar ,&nbsp;Sandip B. Bharate","doi":"10.1016/j.bioorg.2024.108111","DOIUrl":"10.1016/j.bioorg.2024.108111","url":null,"abstract":"<div><div>Cyclin-dependent kinases, CDK7 and CDK9 play critical roles in cancer by regulating transcriptional processes essential for cell proliferation and survival. Their dysregulation leads to aberrant gene expression, promoting oncogenic pathways and contributing to tumor growth and progression. This study aimed to identify a new chemotype for CDK7/9 inhibitors using a structure-based virtual screening approach. Our research led to the discovery of mitoxantrone as an inhibitor of CDK7/H and CDK9/T1 from a library of FDA-approved small molecule drugs. Mitoxantrone, a chemotherapy agent used to treat acute nonlymphocytic leukemia, works by disrupting DNA synthesis and repair, thus inhibiting cancer cell growth. The study found that mitoxantrone effectively inhibits both CDK7/H and CDK9/T1 with IC₅₀ values of 0.675 µM and 5.15 µM, respectively, while showing no inhibition of CDK2/E1 (IC₅₀ &gt; 100 µM) in <em>in-vitro</em> ADP-Glo kinase assay. It binds to the ATP pocket of CDK7 and CDK9, forming crucial H-bonds with MET 94 and CYS 106, respectively. It achieves dock scores of − 12.93 and − 12.59 kcal/mol, and MMGBSA binding energies of − 82.87 and − 81.59 kcal/mol, respectively. Molecular dynamics simulations over 100 ns confirmed stable interactions with MET 94 and CYS 106 in the hinge region of CDK7 and CDK9. The active site sequence alignment helped to understand the differential activity of mitoxantrone for CDK7, 9 and 2 inhibitions. The findings of the paper reveal a novel mechanism of mitoxantrone action that may contribute to its anticancer efficacy.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108111"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2-Acylpyrrole-based alkaloids from the leaves of Sauropus spatulifolius and their α-glucosidase inhibitory activities","authors":"Xiao Xia ,&nbsp;Yan Lu ,&nbsp;Dao-Feng Chen","doi":"10.1016/j.bioorg.2025.108134","DOIUrl":"10.1016/j.bioorg.2025.108134","url":null,"abstract":"<div><div>Pyrrole alkaloids are a class of natural products with intriguing structures and promising biological actives. Within the <em>Sauropus</em> plants, these alkaloids are mainly present in <em>Sauropus spatulifolius</em>. An investigation of the leaves of <em>S. spatulifolius</em> <!-->was conducted to discover novel and bioactive pyrrole alkaloids. This study led to the identification of 38 alkaloids, including 21 new pyrrole alkaloids (<strong>1</strong> − <strong>5</strong>, <strong>13</strong>, <strong>16</strong>, <strong>19</strong> − <strong>23</strong>, <strong>26</strong> − <strong>31</strong>, <strong>33</strong>, <strong>35</strong>, and <strong>36</strong>), along with 17 related analogues (<strong>6</strong> − <strong>12</strong>, <strong>14</strong>, <strong>15</strong>, <strong>17</strong>, <strong>18</strong>, <strong>24</strong>, <strong>25</strong>, <strong>32</strong>, <strong>34 37</strong>, and <strong>38</strong>). The structures of the new compounds were elucidated by NMR, HRESIMS, electronic circular dichroism (ECD), and X-ray diffraction analysis. Notably, compounds <strong>28</strong> − <strong>31</strong> were identified as pyrrole alkaloids with unprecedented skeletons. Compounds <strong>28</strong> and <strong>29</strong> featured a 2-acylpyrrole alkaloid and a cinnamic acid heterodimers, while <strong>30</strong> and <strong>31</strong> possessed a pyrrolooxazinone scaffold with a 1,2-hexadecanediol moiety. These structures were rare in plants. Three compounds (<strong>27</strong>, <strong>31</strong>, and <strong>38</strong>) displayed <em>α</em>-glucosidase inhibitory activity. Particularly, compounds <strong>27</strong> (IC₅₀: 320.3 μM) and <strong>31</strong> (IC₅₀: 153.7 μM) exhibited stronger activity than that of acarbose (IC₅₀: 545.9 μM). Molecular docking studies showed the strong interactions of the three bioactive compounds with the <em>α</em>-glucosidase protein. Additionally, compounds <strong>27</strong>, <strong>31</strong>, and <strong>38</strong> showed significant effects on enhancing glucose consumption in HepG2 cells.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108134"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis, biological evaluation, and in silico studies of phenyl naphthalene-2-sulfonate derived thiosemicarbazones as potential carbonic anhydrase inhibitors","authors":"Javeria Eshal ,&nbsp;Hafiza Zara Tariq ,&nbsp;Jing Li ,&nbsp;Hina Aftab ,&nbsp;Halil Şenol ,&nbsp;Parham Taslimi ,&nbsp;Nastaran Sadeghian ,&nbsp;Rima D. Alharthy ,&nbsp;Muhammad Safwan Akram ,&nbsp;Rimsha Talib ,&nbsp;Zahid Shafiq","doi":"10.1016/j.bioorg.2024.108118","DOIUrl":"10.1016/j.bioorg.2024.108118","url":null,"abstract":"<div><div>A series of novel phenyl naphthalene-2-sulfonate-based thiosemicarbazones <strong>(5a-v)</strong> were synthesized and evaluated for their inhibitory activity against human carbonic anhydrases I and II (hCA I and hCA II). Compounds <strong>5d</strong> and <strong>5p</strong> demonstrated the highest inhibitory potency, with IC₅₀ values of 4.32 ± 0.02 nM and 5.24 ± 0.03 nM for hCA I, and 3.89 ± 0.01 nM and 4.72 ± 0.01 nM for hCA II, respectively. Notably, compound <strong>5d</strong> exhibited superior potency compared to the reference drug acetazolamide. The structure–activity relationship (SAR) analysis revealed that electron-withdrawing groups, particularly the dichlorophenyl group in <strong>5d</strong> and <strong>5p</strong>, enhanced inhibitory activity. Molecular docking and molecular dynamics simulations confirmed the high binding affinity of compound <strong>5d</strong>, with docking scores of −9.7 kcal/mol for hCA I and −9.5 kcal/mol for hCA II. Stability in MD simulations further supported its potent inhibitory action. ADMET predictions suggested that compounds <strong>5d</strong> and <strong>5p</strong> have favorable pharmacokinetic profiles. In conclusion, phenyl naphthalene-2-sulfonate-based thiosemicarbazones, especially compound <strong>5d</strong>, show strong potential as therapeutic agents targeting hCA I and hCA II.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108118"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142963361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}