Drug Development Research最新文献

{"title":"Recombinant human epidermal growth factor-loaded liposomes and transferosomes for dermal delivery: Development, characterization, and cytotoxicity evaluation","authors":"Yasaman Kiani Doustvaghe,&nbsp;Azadeh Haeri,&nbsp;Mahsa Mollapour Sisakht,&nbsp;Mohammad Amir Amirkhani,&nbsp;Hossein Vatanpour","doi":"10.1002/ddr.22234","DOIUrl":"10.1002/ddr.22234","url":null,"abstract":"<p>Recombinant human epidermal growth factor (rhEGF) is widely utilized as an antiaging compound in wound-healing therapies and cosmetic purposes. However, topical administration of rhEGF has limited treatment outcomes because of its poor percutaneous penetration and rapid proteinase degradation. To overcome these obstacles, this study aims to develop and characterize rhEGF-containing conventional liposomes (rhEGF-CLs) and transferosomes (rhEGF-TFs) as efficient dermal carriers. Physicochemical characterization such as particle size, zeta potential (ZP), morphology, encapsulation efficiency (EE%), and release properties of nanocarriers as well as in vitro cytotoxicity in human dermal fibroblast (HDF) and human embryonic kidney (HEK293) cell lines were investigated. rhEGF-TFs at the rhEGF concentration ranging from 0.05 to 1.0 μg/mL were chosen as the optimum formulation due to the desired release profile, acceptable EE%, optimal cell proliferation, and minimal cytotoxicity compared to the control and free rhEGF. However, higher concentrations caused a decrease in cell viability. The ratio 20:80 of Tween 80 to lipid was optimal for rhEGF-TFs-2, which had an average diameter of 233.23 ± 2.64 nm, polydispersity index of 0.33 ± 0.05, ZP of −15.46 ± 0.29 mV, and EE% of 60.50 ± 1.91. The formulations remained stable at 5°C for at least 1 month. TEM and SEM microscopy revealed that rhEGF-TFs-2 had a regular shape and unilamellar structure. In vitro drug release studies confirmed the superiority of rhEGF-TFs-2 in terms of optimal cumulative release of rhEGF approximately 82% within 24 h. Franz diffusion cell study showed higher rhEGF-TFs-2 skin permeation compared to free rhEGF solution. Taken together, we concluded that rhEGF-TFs can be used as a promising formulation for wound healing and skin regeneration products.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 5","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141747733","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 novel cinnamic and caffeic acid-conjugated peptide analogs with anticonvulsant and analgesic potency: Comparative analyses of trans/cis isomers","authors":"Jana Tchekalarova,&nbsp;Daniela Pechlivanova,&nbsp;Miroslav Rangelov,&nbsp;Nadezda Todorova,&nbsp;Tsveta Stoyanova,&nbsp;Borislav Assenov,&nbsp;Petar Todorov","doi":"10.1002/ddr.22236","DOIUrl":"10.1002/ddr.22236","url":null,"abstract":"<p>The novel cinnamic acid (CA) (<b>H4-CA, H5-CA</b>, and <b>H7-CA</b>) and caffeic acid (KA) (<b>H4-KA, H5-KA</b>, and <b>H7-KA</b>) hemorphin analogs have recently been synthesized and their trans isomers have been tested for antiseizure and antinociceptive activity. In the present study, the cis forms of these compounds were tested and compared with their trans isomers in seizure and nociception tests in mice. The cis-<b>H5-CA</b> and <b>H7-CA</b> compounds showed efficacy against psychomotor seizures, whereas the trans isomers were ineffective. Both the cis and trans KA isomers were ineffective in the 6-Hz test. In the maximal electroshock (MES) test, the cis isomers showed superior antiseizure activity to the trans forms of CA and KA conjugates, respectively. The suppression of seizure propagation by cis-<b>H5-CA</b> and the cis-<b>H5-KA</b> was reversed by a kappa opioid receptor (KOR) antagonist. Naloxone and naltrindole were not effective. The cis-isomers of CA conjugates and cis-<b>H7-KA</b> produced significantly stronger antinociceptive effects than their trans-isomers. The cis-<b>H5-CA</b> antinociception was blocked by naloxone in the acute phase and by naloxone and KOR antagonists in the inflammatory phase of the formalin test. The antinociception of the KA conjugates was not abolished by opioid receptor blockade. None of the tested conjugates affected the thermal nociceptive threshold. The results of the docking analysis also suggest a model-specific mechanism related to the activity of the cis-isomers of CA and KA conjugates in relation to opioid receptors. Our findings pave the way for the further development of novel opioid-related antiseizure and antinociceptive therapeutics.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 5","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141731105","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":"Design of novel broad-spectrum antiviral nucleoside analogues using natural bases ring-opening strategy","authors":"Xingyi Du,&nbsp;Xingxing Yang,&nbsp;Jianyuan Zhao,&nbsp;Jinyan Zhang,&nbsp;Jiahui Yu,&nbsp;Ling Ma,&nbsp;Weina Zhang,&nbsp;Shan Cen,&nbsp;Xuhong Ren,&nbsp;Xinhua He","doi":"10.1002/ddr.22237","DOIUrl":"10.1002/ddr.22237","url":null,"abstract":"<p>The global prevalence of RNA virus infections has presented significant challenges to public health in recent years, necessitating the expansion of its alternative therapeutic library. Due to its evolutional conservation, RNA-dependent RNA polymerase (RdRp) has emerged as a potential target for broad-spectrum antiviral nucleoside analogues. However, after over half a century of structural modification, exploring unclaimed chemical space using frequently-used structural substitution methods to design new nucleoside analogues is challenging. In this study, we explore the use of the “ring-opening” strategy to design new base mimics, thereby using these base mimics to design new nucleoside analogues with broad-spectrum antiviral activities. A total of 29 compounds were synthesized. Their activity against viral RdRp was initially screened using an influenza A virus RdRp high-throughput screening model. Then, the antiviral activity of <b>38a</b> was verified against influenza virus strain A/PR/8/34 (H1N1), demonstrating a 50% inhibitory concentration (IC₅₀) value of 9.95 μM, which was superior to that of ribavirin (the positive control, IC₅₀ = 11.43 μM). Moreover, <b>38a</b> also has inhibitory activity against coronavirus 229E with an IC₅₀ of 30.82 μM. In addition, compounds <b>42</b> and <b>46f</b> exhibit an 82% inhibition rate against vesicular stomatitis virus at a concentration of 20 μM and hardly induce cytotoxicity in host cells. This work demonstrates the feasibility of designing nucleoside analogues with “ring-opening” bases and suggests the “ring-opening” nucleosides may have greater polarity, and designing prodrugs is an important aspect of optimizing their antiviral activity. Future research should focus on enhancing the conformational restriction of open-loop bases to mimic Watson-Crick base pairing better and improve antiviral activity.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 5","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141731106","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":"Antiplasmodial action of 4-nitrobenzenesulfonamide chalcones: Design, synthesis, characterisation, in vitro and in silico evaluation against blood stages of Plasmodium falciparum 3D7","authors":"Anju Agnes Tom,&nbsp;Vinoth Rajendran,&nbsp;Ahammed Ameen Thottasseri,&nbsp;Koustav Goswami,&nbsp;Souvik Roy,&nbsp;Gopika Gopan,&nbsp;Maheswaran Mani,&nbsp;Tharanikkarasu Kannan","doi":"10.1002/ddr.22233","DOIUrl":"https://doi.org/10.1002/ddr.22233","url":null,"abstract":"<p>Malaria is an intracellular protozoan parasitic disease caused by <i>Plasmodium</i> species with significant morbidity and mortality in endemic regions. The complex lifecycle of the parasite and the emergence of drug-resistant <i>Plasmodium falciparum</i> have hampered the efficacy of current anti-malarial agents. To circumvent this situation, the present study attempts to demonstrate the blood-stage anti-plasmodial action of 26 hybrid compounds containing the three privileged bioactive scaffolds (sulfonamide, chalcone, and nitro group) with synergistic and multitarget action. These three parent scaffolds exhibit divergent activities, such as antibacterial, anti-malarial, anti-fungal, anti-inflammatory, and anticancer. All the synthesised compounds were characterised using various spectroscopic techniques. The in vitro blood-stage inhibitory activity of 26 hybrid compounds was evaluated against mixed-stage culture (asynchronize) of human malarial parasite <i>P. falciparum, Pf</i> 3D7 at different concentrations ranging from 25.0 µg/mL to 0.78 µg/mL using SYBR 1 green assay, with IC₅₀ values determined after 48 h of treatment based on the drug-response curves. Two potent compounds (<b>11</b> and <b>10</b>), with 2-Br and 2,6-diCl substitutions, showed pronounced activity with IC₅₀ values of 5.4 µg/mL and 5.6 µg/mL, whereas others displayed varied activity with IC₅₀ values ranging from 7.0 µg/mL to 22.0 µg/mL. Both <b>11</b> and <b>10</b> showed greater susceptibility towards mature-stage trophozoites than ring-stage parasites. The hemolytic and in vitro cytotoxicity assays revealed that compounds <b>11</b> and <b>10</b> did not cause any toxic effects on host red blood cells (uninfected), human-derived Mo7e cells, and murine-derived BA/F3 cells. The in vitro observations are consistent with the in silico studies using <i>P. falciparum</i>-dihydrofolate reductase, where <b>11</b> and <b>10</b> showed a binding affinity of −10.4 Kcal/mol. This is the first report of the hybrid scaffold, 4-nitrobenzenesulfonamide chalcones, demonstrating its potential as an anti-plasmodial agent.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 5","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141730323","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":"Discovery of 5-(1-benzyl-1H-imidazol-4-yl)-1,2,4-oxadiazole derivatives as novel RIPK1 inhibitors via structure-based virtual screening","authors":"Yanzhen Yu,&nbsp;Yunzhen Hu,&nbsp;Huihui Yan,&nbsp;Xin Zeng,&nbsp;Haodong Yang,&nbsp;Lei Xu,&nbsp;Rong Sheng","doi":"10.1002/ddr.22235","DOIUrl":"10.1002/ddr.22235","url":null,"abstract":"<p>RIPK1 plays a key role in necroptosis and is associated with various inflammatory diseases. Using structure-based virtual screening, a novel hit with 5-(1-benzyl-1H-imidazol-4-yl)-1,2,4-oxadiazole scaffold was identified as an RIPK1 inhibitor with an IC₅₀ value of 1.3 μM. Further structure–activity relationship study was performed based on similarity research and biological evaluation. The molecular dynamics simulation of compound <b>2</b> with RIPK1 indicated that it may act as a type II kinase inhibitor. This study provides a highly efficient way to discover novel scaffold RIPK1 inhibitors for further development.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 5","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632908","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":"Study on the role of MYCN in retinoblastoma by inhibiting p53 and activating wnt/βcatenin/Fra-1 signaling pathway by reducing DKK3","authors":"Xinke Chen,&nbsp;Lijuan Ouyang,&nbsp;Ning Ke,&nbsp;Lianhong Pi,&nbsp;Xiyuan Zhou","doi":"10.1002/ddr.22222","DOIUrl":"10.1002/ddr.22222","url":null,"abstract":"<p>Retinoblastoma (RB) is a pediatric malignancy, typically diagnosed at birth or during early childhood. The pathogenesis of RB is marked by the amplification of the Basic Helix–Loop–Helix (BHLH) Transcription Factor MYCN, which serves as a transcriptional regulator capable of binding to Dickkopf 3 (DKK3). However, the precise role of DKK3 in the malignant progression of RB cells caused by MYCN remains elusive. In the present study, the expression of MYCN was either overexpressed or interfered in RB cells. Subsequently, the expression level of DKK3 was assessed through quantitative real-time polymerase chain reaction and western blot analysis. Cell proliferation was evaluated using the Cell Counting Kit-8 assay and 5-ethynyl-2′-deoxyuridine staining, while cell cycle progression and apoptosis were analyzed by flow cytometry and western blot analysis, respectively. Additionally, the expression of proteins involved in the Wnt/β-catenin/Fra-1/p53 signaling pathway was evaluated via western blot analysis. To gain further insights, Wnt agonists and the P53 inhibitor PFT-α were introduced into exploration. The current investigation revealed a negative correlation between the expression levels of MYCN and DKK3 in RB cells. Additionally, DKK3 overexpression inhibited cell proliferation, promoted cell apoptosis, and arrested cell cycle in RB cells with high expression of MYCN. Moreover, enhanced DKK3 expression inhibited proliferation, promoted cell cycle arrest and apoptosis of RB cells by modulating the wnt/βcatenin/Fra-1/p53 signaling pathway. Furthermore, in vivo experiments revealed that overexpression of DKK3 inhibits the growth of RB tumors. Collectively, our findings elucidate that MYCN stimulates the Wnt/β-catenin/Fra-1 pathway by suppressing DKK3 expression, ultimately suppressing p53 activity and contributing to malignant progression of RB.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 5","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603436","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":"Identification of aryl hydrocarbon receptor allosteric antagonists from clinically approved drugs","authors":"Farag E. S. Mosa,&nbsp;Mohammed A. Alqahtani,&nbsp;Mahmoud A. El-Ghiaty,&nbsp;Jason R. B. Dyck,&nbsp;Khaled Barakat,&nbsp;Ayman O. S. El-Kadi","doi":"10.1002/ddr.22232","DOIUrl":"10.1002/ddr.22232","url":null,"abstract":"<p>The human aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, plays a pivotal role in a diverse array of pathways in biological and pathophysiological events. This position AhR as a promising target for both carcinogenesis and antitumor strategies. In this study we utilized computational modeling to screen and identify FDA-approved drugs binding to the allosteric site between α2 of bHLH and PAS-A domains of AhR, with the aim of inhibiting its canonical pathway activity. Our findings indicated that nilotinib effectively fits into the allosteric pocket and forms interactions with crucial residues F82, Y76, and Y137. Binding free energy value of nilotinib is the lowest among top hits and maintains stable within its pocket throughout entire (MD) simulations time. Nilotinib has also substantial interactions with F295 and Q383 when it binds to orthosteric site and activate AhR. Surprisingly, it does not influence AhR nuclear translocation in the presence of AhR agonists; instead, it hinders the formation of the functional AhR-ARNT-DNA heterodimer assembly, preventing the upregulation of regulated enzymes like CYP1A1. Importantly, nilotinib exhibits a dual impact on AhR, modulating AhR activity via the PAS-B domain and working as a noncompetitive allosteric antagonist capable of blocking the canonical AhR signaling pathway in the presence of potent AhR agonists. These findings open a new avenue for the repositioning of nilotinib beyond its current application in diverse diseases mediated via AhR.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 5","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.22232","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141589910","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":"Inhibition of the TCF12/VSIG4 axis by palbociclib diminishes the proliferation and migration of glioma cells and decreases the M2 polarization of glioma-associated microglia","authors":"Chuankun Li,&nbsp;Ruichun Li,&nbsp;Yuan Wang,&nbsp;Haitao Jiang","doi":"10.1002/ddr.22230","DOIUrl":"10.1002/ddr.22230","url":null,"abstract":"<p>The CDK4/CDK6 inhibitor palbociclib has shown the encouraging promise in the treatment of glioma. Here, we elucidated how palbociclib exerts suppressive functions in the M2 polarization of glioma-related microglia and the progression of glioma. Xenograft experiments were used to evaluate the function in vivo. The mRNA levels of transcription factor 12 (TCF12) and VSIG4 were detected by RT-qPCR, and their protein levels were assessed by immunoblotting. Cell migration was tested by wound-healing assay. Cell cycle distribution and M1/M2 microglia phenotype analysis were performed by flow cytometry. The levels of IFN-γ, TNF-α, IL-6，and TGF-β were measured by ELISA. The TCF12/VSIG4 association was verified by luciferase reporter and chromatin immunoprecipitation (ChIP) assays. In U251 and LN229 glioma cells, TCF12 and VSIG4 were overexpressed, and palbociclib reduced their expression levels. TCF12 upregulation enhanced the proliferation and migration of glioma cells and the M2 polarization of glioma-associated microglia in vitro as well as the tumorigenicity of U251 glioma cells in vivo, which could be reversed by palbociclib. Mechanistically, TCF12 could enhance VSIG4 transcription and expression by binding to the VSIG4 promoter. TCF12 deficiency led to repression in glioma cell proliferation and migration as well as microglia M2 polarization, which could be abolished by increased VSIG4 expression. Our study reveals the novel TCF12/VSIG4 axis responsible for the efficacy of palbociclib in combating glioma, offering a rationale for the application of palbociclib in glioma treatment.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 5","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533958","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":"Preliminary evaluation of antiproliferative and apoptotic activities of novel indolin-2-one derivatives","authors":"Gulseren Turhal,&nbsp;Busra Demirkan,&nbsp;Izel Nermin Baslilar,&nbsp;Nimet Sule Yuncu,&nbsp;Sultan Nacak Baytas,&nbsp;Asuman Demiroglu-Zergeroglu","doi":"10.1002/ddr.22229","DOIUrl":"10.1002/ddr.22229","url":null,"abstract":"<p>Indole-based agents are frequently used in targeted or supportive therapy of several cancers. In this study, we investigated the anticancer properties of originally synthesized novel indolin-2-one derivatives (<i><b>6a-d</b></i>) against Malignant Mesothelioma, Breast cancer, and Colon Cancer cells. Our results revealed that all derivatives were effectively delayed cell proliferation by inhibiting the ERK1/2, AKT, and STAT3 signaling pathways in a concentration-dependent manner. Additionally, these variants induced cell cycle arrest in the S phase, accompanied by elevated levels of p21 and p27 expressions. Derivatives also initiated mitochondrial apoptosis through the upregulation of Bax and downregulation of Bcl-2 proteins, leading to the activation of caspase 3 and PARP cleavage in exposed cells. Remarkably, three of the indolin-2-one derivatives displayed significant selectivity towards Breast and Colon Cancer cells, with compound <i><b>6d</b></i> promising as the most potent and wide spectral one for all cancer cell lines.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 5","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.22229","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141491305","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":"Novel 1,3,4-oxadiazole derivatives of naproxen targeting EGFR: Synthesis, molecular docking studies, and cytotoxic evaluation","authors":"Hiba N. Alsaad,&nbsp;Baan M. AL-Jasani,&nbsp;Ammar A. Razzak Mahmood,&nbsp;Lubna H. Tahtamouni,&nbsp;Khaled M. Saleh,&nbsp;Mai F. AlSakhen,&nbsp;Sana I. Kanaan,&nbsp;Salem R. Yasin","doi":"10.1002/ddr.22231","DOIUrl":"10.1002/ddr.22231","url":null,"abstract":"<p>The close association between inflammation and cancer inspired the synthesis of a series of 1,3,4-oxadiazole derivatives (compounds <b>H4-A-F</b>) of 6-methoxynaphtalene. The chemical structures of the new compounds were validated utilizing Fourier-transform infrared, proton nuclear magnetic resonance, and carbon-13 nuclear magnetic resonance spectroscopic techniques and CHN analysis. Computer-aided drug design methods were used to predict the compounds biological target, ADMET properties, toxicity, and to evaluate the molecular similarities between the design compounds and erlotinib, a standard epidermal growth factor receptor (EGFR) inhibitor. The antiproliferative effects of the new compounds were evaluated by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay, cell cycle analysis, apoptosis detection by microscopy, quantitative reverse transcription-polymerase chain reaction, and immunoblotting, and EGFR enzyme inhibition assay. In silico analysis of the new oxadiazole derivatives indicated that these compounds target EGFR, and that compounds <b>H4-A</b>, <b>H4-B</b>, <b>H4-C</b>, and <b>H4-E</b> show similar molecular properties to erlotinib. Additionally, the results indicated that none of the synthesized compounds are carcinogenic, and that compounds <b>H4-A</b>, <b>H4-C</b>, and <b>H4-F</b> are nontoxic. Compound <b>H4-A</b> showed the best-fit score against EGFR pharmacophore model, however, the in vitro studies indicated that compound <b>H4-C</b> was the most cytotoxic. Compound <b>H4-C</b> caused cytotoxicity in HCT-116 colorectal cancer cells by inducing both apoptosis and necrosis. Furthermore, compounds <b>H4-D, H4-C</b>, and <b>H4-B</b> had potent inhibitory effect on EGFR tyrosine kinase that was comparable to erlotinib. The findings of this inquiry offer a basis for further investigation into the differences between the synthesized compounds and erlotinib. However, additional testing will be needed to assess all of these differences and to identify the most promising compound for further research.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 5","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141491304","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}