MedChemComm最新文献

{"title":"Strong in vitro anticancer activity of copper(ii) and zinc(ii) complexes containing naturally occurring lapachol: cellular effects in ovarian A2780 cells†‡","authors":"Sara Stocchetti, Ján Vančo, Jan Belza, Zdeněk Dvořák and Zdeněk Trávníček","doi":"10.1039/D4MD00543K","DOIUrl":"10.1039/D4MD00543K","url":null,"abstract":"<p >Copper(<small>II</small>) and zinc(<small>II</small>) complexes with lapachol (HLap) of the composition [M(Lap)<small>₂</small>(N–N)] and [Cu(Lap)(H<small>₂</small>O)(terpy)]NO<small>₃</small> (<strong>4</strong>), where M = Cu (<strong>1–3</strong>) or Zn (for <strong>5–7</strong>), and N–N stands for bathophenanthroline (<strong>1</strong> and <strong>5</strong>), 5-methyl-1,10-phenanthroline (<strong>2</strong> and <strong>6</strong>), 2,2′-bipyridine (<strong>3</strong>), 2,2′;6′,2′′-terpyridine (terpy, <strong>4</strong>) and 1,10-phenanthroline (<strong>7</strong>), were synthesised and characterised. Complexes <strong>1–5</strong> revealed strong <em>in vitro</em> antiproliferative effects against A2780, A2780R, MCF-7, PC-3, A549 and HOS human cancer lines and MRC-5 normal cells, with IC<small>₅₀</small> values above 0.5 μM, and reasonable selectivity index (SI), with SI &gt; 3.8 for IC<small>₅₀</small>(MRC-5)/IC<small>₅₀</small>(A2780). Considerable time-dependent cytotoxicity in A2780 cells was observed for complexes <strong>6</strong> and <strong>7</strong>, with IC<small>₅₀</small> &gt; 50 μM (24 h) to <em>ca.</em> 4 μM (48 h). Cellular effects of complexes <strong>1</strong>, <strong>5</strong> and <strong>7</strong> in A2780 cells were investigated by flow cytometry revealing that the most cytotoxic complexes (<strong>1</strong> and <strong>5</strong>) significantly perturbed the mitochondrial membrane potential and the interaction with mitochondrial metabolism followed by the triggering of the intracellular pathway of apoptosis.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 12","pages":" 4180-4192"},"PeriodicalIF":3.597,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11451940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rationally modified SNX-class Hsp90 inhibitors disrupt extracellular fibronectin assembly without intracellular Hsp90 activity†","authors":"Gciniwe S. Mathenjwa, Abir Chakraborty, Abantika Chakraborty, Ronel Muller, Mathew P. Akerman, Moira L. Bode, Adrienne L. Edkins and Clinton G. L. Veale","doi":"10.1039/D4MD00501E","DOIUrl":"10.1039/D4MD00501E","url":null,"abstract":"<p >Despite Hsp90's well documented promise as a target for developing cancer chemotherapeutics, its inhibitors have struggled to progress through clinical trials. This is, in part, attributed to the cytoprotective compensatory heat shock response (HSR) stimulated through intracellular Hsp90 inhibition. Beyond its intracellular role, secreted extracellular Hsp90 (eHsp90) interacts with numerous pro-oncogenic extracellular clients. This includes fibronectin, which in the tumour microenvironment enhances cell invasiveness and metastasis. Through the rational modification of known Hsp90 inhibitors (SNX2112 and SNX25a) we developed four Hsp90 inhibitory compounds, whose alterations restricted their interaction with intracellular Hsp90 and did not stimulate the HSR. Two of the modified cohort (compounds <strong>10</strong> and <strong>11</strong>) were able to disrupt the assembly of the extracellular fibronectin network at non-cytotoxic concentrations, and thus represent promising new tool compounds for studying the druggability of eHsp90 as a target for inhibition of tumour invasiveness and metastasis.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 10","pages":" 3609-3615"},"PeriodicalIF":3.597,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00501e?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design and synthesis of novel multi-target tetrabromophthalimides as CBS and Topo-II inhibitors and DNA intercalators†","authors":"Marwa Abdel-Motaal, Dalal Ali Aldakhili, Ayman B. Farag, Ayman Abo Elmaaty, Marwa Sharaky, Nadia A. Mohamed, Saad Shaaban, Abdullah Yahya Abdullah Alzahrani and Ahmed A. Al-Karmalawy","doi":"10.1039/D4MD00585F","DOIUrl":"10.1039/D4MD00585F","url":null,"abstract":"<p >Microtubules are highly dynamic structures and constitute a crucial component of the cellular cytoskeleton. Besides, topoisomerases (Topo) play a fundamental role in maintaining the appropriate structure and organization of DNA. On the other hand, dual mechanism drug candidates for cancer treatment primarily aim to enhance the efficacy of cancer treatment and potentially overcome drug resistance. Hence, this work was tailored to design and synthesize new multi-target tetrabromophthalimide derivatives (<strong>2a–2k</strong>) that are capable of inhibiting the colchicine binding site (CBS) and topoisomerase II (Topo-II). The conducted <em>in vitro</em> studies showed that compound <strong>2f</strong> showed the lowest IC<small>₅₀</small> value (6.7 μg mL<small>⁻¹</small>) against the MDA-MB-468 cancer cell line. Additionally, compound <strong>2f</strong> prompted upregulation of pro-apoptotic markers (caspases 3, 7, 8, and 9, Bax and p53). Moreover, some anti-apoptotic proteins (MMP2, MMP9, and BCL-2) were downregulated by compound <strong>2f</strong> treatment. Besides, the colchicine binding assay showed that compounds <strong>2f</strong> and <strong>2k</strong> displayed promising inhibitory potential with IC<small>₅₀</small> values of 1.92 and 4.84 μg mL<small>⁻¹</small>, respectively, in comparison with colchicine (1.55 μg mL<small>⁻¹</small>). Furthermore, the Topo-II inhibition assay displayed the prominent inhibitory potential of compound <strong>2f</strong> with an IC<small>₅₀</small> value of 15.75 μg mL<small>⁻¹</small>, surpassing the IC<small>₅₀</small> of etoposide (20.82 μg mL<small>⁻¹</small>). Cell cycle analysis revealed that compound <strong>2f</strong> induced cell cycle arrest at both the G0–G1 and G2–M phases. The new candidates were docked against both the CBS (PDB ID: 5XIW) and Topo-II (PDB ID: 5CDP) targets to investigate their binding interactions and affinities as well. Accordingly, the synthesized compounds could serve as promising multi-target anticancer candidates with eligible apoptotic activity.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 11","pages":" 3800-3816"},"PeriodicalIF":3.597,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pyridinyl 4-(2-oxoalkylimidazolidin-1-yl)benzenesulfonates and their hydrochloride salts as novel water soluble antimitotic prodrugs bioactivated by cytochrome P450 1A1 in breast cancer cells†","authors":"Vincent Ouellette, Chahrazed Bouzriba, Atziri Corin Chavez Alvarez, Quentin Bruxelles, Geneviève Hamel-Côté and Sébastien Fortin","doi":"10.1039/D4MD00476K","DOIUrl":"10.1039/D4MD00476K","url":null,"abstract":"<p >We developed first-in-class antimitotic prodrugs phenyl 4-(2-oxo-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) bioactivated by cytochrome P450 (CYP) 1A1 that are highly selective toward several breast cancer cells. However, they show sparingly water solubility. Therefore, we replaced their phenyl ring B with a substituted pyridinyl group preparing novel pyridinyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PYRAIB-SOs) and their hydrochloride salts. Our results evidence that PYRAIB-SO hydrochloride salts show higher water solubility compared to their neutral and PAIB-SO counterparts by up to 625-fold. PYRAIB-SOs with a nitrogen atom at position 3 of the pyridinyl ring exhibited strong antiproliferative activity (IC<small>₅₀</small>: 0.03–3.3 μM) and high selectivity (8–&gt;1250) toward sensitive CYP1A1-positive breast cancer cells and cells stably transfected with CYP1A1. They induce cell cycle arrest in the G2/M phase and disrupt microtubule dynamic assembly. Enzymatic assays confirmed that CYP1A1 metabolizes PYRAIB-SOs into their active form with <em>in vitro</em> hepatic half-lives (55–120 min) in rodent and human liver microsomes. Overall, this will allow to increase drug concentration for <em>in vivo</em> studies.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 11","pages":" 3728-3745"},"PeriodicalIF":3.597,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stachydrine, a pyrrole alkaloid with promising therapeutic potential against metabolic syndrome and associated organ dysfunction","authors":"Semim Akhtar Ahmed, Prasenjit Manna and Jagat Chandra Borah","doi":"10.1039/D4MD00425F","DOIUrl":"10.1039/D4MD00425F","url":null,"abstract":"<p >Metabolic syndrome is a multifaceted condition marked by interconnected risk factors, significantly increasing the risk of serious diseases like cardiovascular disease, type 2 diabetes, and stroke. Effective management often demands new medications due to complexity of the conditions and limitations of current treatments. Natural compounds are increasingly recognized in drug discovery due to their vast chemical diversity, commercial availability, low cost, and minimal side effects. One such compound is stachydrine (STA), also known as proline betaine or <em>N</em>-dimethyl proline. This simple pyrrole alkaloid is a major constituent of the genus <em>Leonurus</em> and the family Lamiaceae, and it shows promise due to its potential therapeutic properties. A comprehensive review of the literature, sourced from databases such as PubMed, Scopus, SciFinder, and Google Scholar, has provided extensive information on the sources, chemistry, biosynthesis, derivatives, molecular targets, biological activities, bioavailability, and toxicity of STA. This review highlights numerous <em>in vitro</em> and <em>in vivo</em> studies that demonstrate the effectiveness of STA in various therapeutic areas, including anti-obesity, neuroprotective, nephroprotective, and cardiovascular protection, among others. The wide range of biological activities of STA is attributed to its influence on multiple molecular targets and signaling pathways, such as ACE/AngII/AT1R-TGFβ1, NF-κB, JAK/STAT, AKT/ERK, AMPK/CAMKKβ/LKB1, CaMKII/PLN, <em>etc.</em> which are critical in the development and progression of metabolic syndrome. Additionally, this review addresses limitations related to the pharmacokinetics and bioavailability of STA. Overall, the findings underscore the potential of STA as a therapeutic agent for metabolic syndrome and related disorders, suggesting that further clinical investigation is warranted to fully understand and utilize its benefits.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 11","pages":" 3652-3673"},"PeriodicalIF":3.597,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preventing SARS-CoV-2 infection using Fv-antibodies targeting the proprotein convertase (PPC) cleavage site","authors":"Jaeyong Jung, Jeong Soo Sung, Soonil Kwon, Hyung Eun Bae, Min-Jung Kang, Joachim Jose, Misu Lee and Jae-Chul Pyun","doi":"10.1039/D4MD00552J","DOIUrl":"10.1039/D4MD00552J","url":null,"abstract":"<p >Fv-antibodies targeting the proprotein convertase (PPC) region of the SARS-CoV-2 spike protein (SP) were screened from an Fv-antibody library to inhibit SARS-CoV-2 infection. Two selected Fv-antibodies were expressed as soluble recombinant proteins, and their binding affinities were assessed using a surface plasmon resonance biosensor. The binding regions of these Fv-antibodies corresponded to the cleavage sites of furin (S1/S2) and transmembrane serine protease 2 (TMPRSS2, S2′). The neutralizing activities of the two Fv-antibodies were demonstrated using a cell-based infection assay with pseudo-viruses carrying the SP of four different SARS-CoV-2 variants: wild-type (D614), delta (B.1.617.2), omicron (BA.2), and omicron (BA.4/5).</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 11","pages":" 3704-3710"},"PeriodicalIF":3.597,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis and biological evaluation of a novel PSMA–PI3K small molecule drug conjugate†","authors":"Shouguo Peng, Haixia Li, Weilu Cui, Tianning Xiong, Jiaqi Hu, Haixiang Qi, Songwen Lin, Deyu Wu, Ming Ji and Heng Xu","doi":"10.1039/D4MD00246F","DOIUrl":"10.1039/D4MD00246F","url":null,"abstract":"<p >Small molecule drug conjugates are an emerging targeted therapy for cancer treatment. Building upon the overexpressed prostate-specific membrane antigen (PSMA) in prostate cancer, we herein report the design and synthesis of a novel PSMA–PI3K small molecule drug conjugate <strong>1</strong>. Conjugate <strong>1</strong> demonstrates potent inhibition against PI3K with an IC<small>₅₀</small> value of 0.40 nM and simultaneously targets PSMA, giving rise to selective growth inhibition activity for PSMA-positive cancer cells. Conjugate <strong>1</strong> also potently inhibits the phosphorylation of PI3K main downstream effectors and arrests the cell cycle in the G0/G1 phase in PSMA-positive 22Rv1 prostate cancer cells. Further <em>in vivo</em> evaluation shows that conjugate <strong>1</strong> has favorable efficacy and tolerability in a 22Rv1 xenograft model, demonstrating its potential application in targeted cancer therapy.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 10","pages":" 3485-3494"},"PeriodicalIF":3.597,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Furoxan–piplartine hybrids as effective NO donors and ROS inducers in PC3 cancer cells: design, synthesis, and biological evaluation†","authors":"Carolyne Brustolin Braga, Julio Cesar Milan, Matheus Andrade Meirelles, Bruno Zavan, Guilherme Álvaro Ferreira-Silva, Ester Siqueira Caixeta, Marisa Ionta and Ronaldo A. Pilli","doi":"10.1039/D4MD00281D","DOIUrl":"10.1039/D4MD00281D","url":null,"abstract":"<p >Conjugation of the naturally occurring product piplartine (PPT, <strong>1</strong>), which is a potent cytotoxic compound and ROS inducer, with a diphenyl sulfonyl-substituted furoxan moiety (namely, 3,4-bis(phenylsulfonyl)-1,2,5-oxadiazole-2-oxide), an important type of NO donor, <em>via</em> an ether linker of different chain lengths is described, characterized and screened for the anticancer potential. The cytotoxicity of the new hybrids was evaluated on a panel of human cancer cell lines (MCF-7, PC3 and OVCAR-3) and two non-cancer human cells (MCF10A and PNT2). In general, the synthesized hybrids were more cytotoxic and selective compared to their furoxan precursors <strong>4–6</strong> and PPT in the above cancer cells. Particularly, PC3 cells are the most sensitive to hybrids <strong>7</strong> and <strong>9</strong> (IC<small>₅₀</small> values of 240 nM and 50 nM, respectively), while a lower potency was found for the prostate normal cells (IC<small>₅₀</small> = 17.8 μM and 14.1 μM, respectively), corresponding to selectivity indices of <em>ca.</em> 75 and 280, respectively. NO generation by the PPT–furoxan compounds in PC3 cells was confirmed using the Griess reaction. Furthermore, the cell growth inhibitory effect of <strong>9</strong> was significantly attenuated by the NO scavenger carboxy-PTIO. The intracellular ROS generation by <strong>7</strong> and <strong>9</strong> was also verified, and different assays showed that co-treatment with the antioxidant <em>N</em>-acetyl-<small>L</small>-cysteine (NAC) provided protection against PPT-induced ROS generation. Further mechanistic studies revealed that <strong>7</strong> and <strong>9</strong> had strong cytotoxicity to induce apoptosis in PC3 cells, being mediated, at least in part, by the NO-release and increase in ROS production. Notably, the ability of <strong>9</strong> to induce apoptosis was stronger than that of <strong>7</strong>, which may be attributed to higher levels of NO released by <strong>9</strong>. Compounds <strong>7</strong> and <strong>9</strong> modulated the expression profiles of critical regulators of cell cycle, such as <em>CDKN1A</em> (p21), <em>c-MYC</em>, and <em>CCND1</em> (cyclin D1), as well as induced DNA damage. Overall, tethering the furoxan NO-releasing moiety to the cytotoxic natural product PPT had significant impact on the potential anticancer activity and selectivity of the novel hybrid drug candidates, especially <strong>9</strong>, as a result of synergistic effects of both furoxan and PPT's ability to release NO, generate ROS, induce DNA damage, and trigger apoptosis.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 11","pages":" 3778-3794"},"PeriodicalIF":3.597,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New ATP-competitive inhibitors of E. coli GyrB obtained from the mapping of the hydrophobic floor at the binding site: synthesis and biological evaluation†","authors":"Lucas Gutierrez, Peter Peršolja, Rodrigo Tosso, Nace Zidar, Danijel Kikelj and Ricardo D. Enriz","doi":"10.1039/D4MD00498A","DOIUrl":"10.1039/D4MD00498A","url":null,"abstract":"<p >We mapped the hydrophobic floor, an interesting subsite at the active site of DNA gyrase B (GyrB) from <em>E. coli</em>. We synthesized three new compounds with pendant groups targeting the hydrophobic floor and evaluated their inhibitory activities on DNA gyrase. A new benzothiazole derivative with a benzyl substituent at position 3 of the benzothiazole ring exhibited strong inhibitory activity against <em>E. coli</em> DNA gyrase (IC<small>₅₀</small> = 19 ± 3 nM). An exhaustive conformational study using potential energy surfaces (PESs) allowed us to map the new subsite evaluating all critical points on the surface and conformational interconversion pathways. We analyzed the molecular interactions using QTAIM calculations. Our data provide insights into the mechanism of action of these new ligands at the molecular level. Theoretical and experimental data suggest that new ligand optimization strategies should focus on strengthening interactions at the hydrophobic floor while preserving the binding mode of the main scaffold.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 11","pages":" 3759-3777"},"PeriodicalIF":3.597,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pyridazinone-based derivatives as anticancer agents endowed with anti-microbial activity: molecular design, synthesis, and biological investigation†","authors":"Mohamed K. S. El-Nagar, Mai I. Shahin, Mohammed F. El-Behairy, Ehab S. Taher, Mohamed F. El-Badawy, Marwa Sharaky, Dalal A. Abou El Ella, Khaled A. M. Abouzid and Mai Adel","doi":"10.1039/D4MD00481G","DOIUrl":"10.1039/D4MD00481G","url":null,"abstract":"<p >Cancer patients undergoing chemotherapy are highly susceptible to infections owing to their compromised immune system, which also promotes cancer progression through inflammation. Thus, this study aimed to develop novel chemotherapeutic agents with both anticancer and antimicrobial properties. A series of diarylurea derivatives based on pyridazinone scaffolds were designed, synthesized, and characterized as surrogates for sorafenib. The synthesized compounds were tested for their antimicrobial activity and screened against 60 cancer cell lines at the National Cancer Institute (NCI). Compound <strong>10h</strong> exhibited potent antibacterial activity against <em>Staphylococcus aureus</em> (MIC = 16 μg mL<small>⁻¹</small>), whereas compound <strong>8g</strong> showed significant antifungal activity against <em>Candida albicans</em> (MIC = 16 μg mL<small>⁻¹</small>). Additionally, ten compounds were further evaluated for VEGFR-2 inhibition, with compound <strong>17a</strong> showing the best inhibitory activity. Compounds <strong>8f</strong>, <strong>10l</strong>, and <strong>17a</strong> demonstrated significant anticancer activity against melanoma, NSCLC, prostate cancer, and colon cancer, with growth inhibition percentages (GI%) ranging from 62.21% to 100.14%. Compounds <strong>10l</strong> and <strong>17a</strong> were selected for five-dose screening, displaying GI<small>₅₀</small> values of 1.66–100 μM. Compound <strong>10l</strong> induced G0–G1 phase cell cycle arrest in the A549/ATCC cell line, increasing the cell population from 85.41% to 90.86%. Gene expression analysis showed that compound <strong>10l</strong> upregulated pro-apoptotic genes p53 and Bax and downregulated the anti-apoptotic gene Bcl-2. Molecular docking studies provided insights into the binding modes of the compounds to the VEGFR-2 enzyme. In conclusion, the pyridazinone-based diarylurea derivatives developed in this study show promise as dual-function antimicrobial and anticancer agents, warranting further investigation.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 10","pages":" 3529-3557"},"PeriodicalIF":3.597,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}