Pub Date : 2026-01-23DOI: 10.1016/j.bmc.2026.118574
Shikha Kaushik , Shrikant Kukreti
Conformational polymorphism exhibited by nucleic acids makes them potential tools in various fields of molecular biology, medicine, nanobiotechnology, and material science. The structural versatility associated with DNA and RNA forms the basis for developing oligonucleotide-based therapeutic strategies. Moreover, DNA's ability to respond to various physicochemical stimuli makes it a suitable candidate for biosensing applications. Naturally, two strands of the B-DNA duplex are oriented antiparallel to each other, stabilized by Watson-Crick hydrogen bonding. However, the formation of non-canonical DNA structures possessing varied base pairing schemes and strand orientation is also possible. Herein, a combination of UV-thermal denaturation, native polyacrylamide gel electrophoresis, and circular dichroism was used to investigate the structures formed by sequence-specific binding of a designed pyrimidine oligonucleotide to the target dodecamer (Pu.Py) segment of the BOLF1 gene of human herpesvirus 4 (HH4) genome. Through a curiosity-driven experiment, we report the formation of a parallel-stranded (ps) duplex at neutral pH, which transforms into a three-stranded DNA structure on lowering the pH. While the ps duplex is facilitated by reverse Watson-Crick; the triplex-DNA structure, formed at low pH, is stabilized by reverse Watson-Crick and Hoogsteen hydrogen bonding, resulting in an all-parallel-strand triple-stranded structure. To the best of our knowledge, any oligomeric structure consisting of all three strands (one Pu and two Py) in parallel orientation has not been characterized to date. Such a pH-mediated structural switching by DNA sequences may provide insights into the bioprocesses involving pH changes, both in vitro and in vivo, and towards the development of pH-based biosensors.
{"title":"pH-induced structural switch of a parallel duplex to triplex-DNA at a BOLF1 gene segment of the human herpes virus 4 (HH4) genome","authors":"Shikha Kaushik , Shrikant Kukreti","doi":"10.1016/j.bmc.2026.118574","DOIUrl":"10.1016/j.bmc.2026.118574","url":null,"abstract":"<div><div>Conformational polymorphism exhibited by nucleic acids makes them potential tools in various fields of molecular biology, medicine, nanobiotechnology, and material science. The structural versatility associated with DNA and RNA forms the basis for developing oligonucleotide-based therapeutic strategies. Moreover, DNA's ability to respond to various physicochemical stimuli makes it a suitable candidate for biosensing applications. Naturally, two strands of the B-DNA duplex are oriented antiparallel to each other, stabilized by Watson-Crick hydrogen bonding. However, the formation of non-canonical DNA structures possessing varied base pairing schemes and strand orientation is also possible. Herein, a combination of UV-thermal denaturation, native polyacrylamide gel electrophoresis, and circular dichroism was used to investigate the structures formed by sequence-specific binding of a designed pyrimidine oligonucleotide to the target dodecamer (Pu.Py) segment of the <em>BOLF1</em> gene of human <em>herpesvirus 4 (HH4)</em> genome. Through a curiosity-driven experiment, we report the formation of a parallel-stranded (ps) duplex at neutral pH, which transforms into a three-stranded DNA structure on lowering the pH. While the ps duplex is facilitated by reverse Watson-Crick; the triplex-DNA structure, formed at low pH, is stabilized by reverse Watson-Crick and Hoogsteen hydrogen bonding, resulting in an all-parallel-strand triple-stranded structure. To the best of our knowledge, any oligomeric structure consisting of all three strands (one Pu and two Py) in parallel orientation has not been characterized to date. Such a pH-mediated structural switching by DNA sequences may provide insights into the bioprocesses involving pH changes, both <em>in vitro</em> and <em>in vivo,</em> and towards the development of pH-based biosensors.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118574"},"PeriodicalIF":3.0,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075111","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}
Pub Date : 2026-01-19DOI: 10.1016/j.bmc.2026.118572
Carla Caroline Ribeiro de Mendonça , Walber Fernandes Ferreira Coutinho , Thiago Lourenco dos Santos , Mirely Vitória Farias da Silva , Gisela C. Paulino , Demétrius A.M. de Araújo , Igor José dos Santos Nascimento , João R. Xavier de Araújo-Júnior , Francisco Jaime Bezerra Mendonça-Junior , Valnês da Silva Rodrigues-Júnior , Edeildo Ferreira da Silva-Júnior
Dihydroquinazolin-4(3H)-imines have emerged as a promising scaffold for developing novel antimycobacterial agents. Here, we integrated QSAR modeling, in vitro screening, molecular dynamics (MD), binding free-energy calculations, and in vivo toxicity assessment to identify potent inhibitors against Mycobacterium tuberculosis (Mtb). Four QSAR models demonstrated strong internal and external reliability (R2> 0.68; Q2LOO> 0.62; R2extup to 0.82). Additional validation parameters met recommended thresholds (Q2-F1/F2/F3 ≥ 0.72; CCCext≥ 0.88; r2m aver≥ 0.72; r2m delta: 0.04), and Williams plots confirmed that all predictions fell within the applicability domain (h*: 0.286). Biological assays identified 11 active compounds, with MIC values ranging from 25 to 200 μM. Compound 2c (p-methylphenyl derivative) and 3d (m, p-dichlorophenyl analog) were the most potent, displaying MIC values of 50 and 25 μM, respectively. MD simulations revealed stable and specific interactions with Eis, an acetyltransferase linked to kanamycin resistance. Compound 2c exhibited a mean ΔGbind of −52.19 ± 3.21 kcal/mol, while 3d showed a more favorable ΔGbind of −73.15 ± 3.16 kcal/mol, consistent with its superior in vitro potency. Distinct interaction profiles—especially the engagement of Tyr126 and hydrophobic clusters—help explain their differential affinities. Moreover, both leads demonstrated low to moderate in vitro cytotoxicity against HepG2 cells at the concentrations evaluated. In vivo acute toxicity in Zophobas morio indicated LD₅₀ values of 500 mg/kg for 2c and 100 mg/kg for 3d, with transient tremors and melanization observed only for 3d. Since compound 2c exhibited a safer in vivo toxicity profile, this compound was investigated for its association with antimicrobial drugs. These compounds were validated as promising anti-TB candidates, supported by robust QSAR predictivity, favorable binding energetics, and measurable in vitro and in vivo toxicity profiles, reinforcing their potentials for further optimization.
{"title":"QSAR-based drug discovery of 2-((4-Imino-3,4-dihydroquinazolin-2-yl)thio-substituted analogs targeting Mycobacterium tuberculosis","authors":"Carla Caroline Ribeiro de Mendonça , Walber Fernandes Ferreira Coutinho , Thiago Lourenco dos Santos , Mirely Vitória Farias da Silva , Gisela C. Paulino , Demétrius A.M. de Araújo , Igor José dos Santos Nascimento , João R. Xavier de Araújo-Júnior , Francisco Jaime Bezerra Mendonça-Junior , Valnês da Silva Rodrigues-Júnior , Edeildo Ferreira da Silva-Júnior","doi":"10.1016/j.bmc.2026.118572","DOIUrl":"10.1016/j.bmc.2026.118572","url":null,"abstract":"<div><div>Dihydroquinazolin-4(3<em>H</em>)-imines have emerged as a promising scaffold for developing novel antimycobacterial agents. Here, we integrated QSAR modeling, <em>in vitro</em> screening, molecular dynamics (MD), binding free-energy calculations, and <em>in vivo</em> toxicity assessment to identify potent inhibitors against <em>Mycobacterium tuberculosis</em> (<em>Mtb</em>). Four QSAR models demonstrated strong internal and external reliability (<em>R</em><sup><em>2</em></sup> <em>> 0.68; Q</em><sup><em>2</em></sup><sub><em>LOO</em></sub> <em>> 0.62; R</em><sup><em>2</em></sup><sub><em>ext</em></sub> <em>up to 0.82</em>). Additional validation parameters met recommended thresholds (Q<sup>2</sup><em>-F1/F2/F3 ≥ 0.72; CCC</em><sub><em>ext</em></sub> <em>≥ 0.88</em>; <em>r</em><sup><em>2</em></sup><sub><em>m aver</em></sub> <em>≥ 0.72; r</em><sup><em>2</em></sup><sub><em>m delta</em></sub><em>: 0.04</em>), and Williams plots confirmed that all predictions fell within the applicability domain (<em>h*: 0.286</em>). Biological assays identified 11 active compounds, with MIC values ranging from 25 to 200 μM. Compound <strong>2c</strong> (<em>p</em>-methylphenyl derivative) and <strong>3d</strong> (<em>m, p</em>-dichlorophenyl analog) were the most potent, displaying MIC values of 50 and 25 μM, respectively. MD simulations revealed stable and specific interactions with Eis, an acetyltransferase linked to kanamycin resistance. Compound <strong>2c</strong> exhibited a mean Δ<em>G</em><sub><em>bind</em></sub> of −52.19 ± 3.21 kcal/mol, while <strong>3d</strong> showed a more favorable Δ<em>G</em><sub><em>bind</em></sub> of −73.15 ± 3.16 kcal/mol, consistent with its superior <em>in vitro</em> potency. Distinct interaction profiles—especially the engagement of Tyr<sup>126</sup> and hydrophobic clusters—help explain their differential affinities. Moreover, both leads demonstrated low to moderate <em>in vitro</em> cytotoxicity against HepG2 cells at the concentrations evaluated. <em>In vivo</em> acute toxicity in <em>Zophobas morio</em> indicated LD₅₀ values of 500 mg/kg for <strong>2c</strong> and 100 mg/kg for <strong>3d</strong>, with transient tremors and melanization observed only for <strong>3d</strong>. Since compound <strong>2c</strong> exhibited a safer <em>in vivo</em> toxicity profile, this compound was investigated for its association with antimicrobial drugs. These compounds were validated as promising anti-TB candidates, supported by robust QSAR predictivity, favorable binding energetics, and measurable <em>in vitro</em> and <em>in vivo</em> toxicity profiles, reinforcing their potentials for further optimization.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118572"},"PeriodicalIF":3.0,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146058341","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}
Pub Date : 2026-01-19DOI: 10.1016/j.bmc.2026.118568
Chenliang Zhao , Yinxiao Du , Yixuan Xia , Baisen Chen , Zhongyi Seng , Kanglun Liu , Chushing Lam , Juan Zou , Hongjie Zhang
Ent-11α-hydroxy-15-oxo-kaur-16-en-19-oic-acid (5F) is a naturally occurring ent-kaurane diterpenoid isolated from the traditional Chinese herbal medicine Pteris semipinnata L., a fern plant known for its reported antitumor properties. In an effort to expand the pool of natural scaffold-based compounds for anticancer purposes, novel derivatives of 5F have been synthesized by modifying functional groups at C-11 and C-19. These derivatives have been evaluated for their anti-proliferative activities against a panel of cancer cell lines. Among them, compound 13 exhibited approximately 27 times greater potency than 5F in HCT116 cells, with an IC50 value of 0.232 μM. In an HCT116 xenograft mouse model, 13 displayed superior tumor inhibitory effects compared to fluorouracil (5-FU).
{"title":"Design, synthesis and biological evaluation of new ent-11α-hydroxy-15-oxo-kaur-16-en-19-oic-acid (5F) derivatives as potential antitumor agents","authors":"Chenliang Zhao , Yinxiao Du , Yixuan Xia , Baisen Chen , Zhongyi Seng , Kanglun Liu , Chushing Lam , Juan Zou , Hongjie Zhang","doi":"10.1016/j.bmc.2026.118568","DOIUrl":"10.1016/j.bmc.2026.118568","url":null,"abstract":"<div><div><em>Ent</em>-11α-hydroxy-15-oxo-kaur-16-en-19-oic-acid (5F) is a naturally occurring <em>ent</em>-kaurane diterpenoid isolated from the traditional Chinese herbal medicine <em>Pteris semipinnata</em> L., a fern plant known for its reported antitumor properties. In an effort to expand the pool of natural scaffold-based compounds for anticancer purposes, novel derivatives of 5F have been synthesized by modifying functional groups at C-11 and C-19. These derivatives have been evaluated for their anti-proliferative activities against a panel of cancer cell lines. Among them, compound <strong>13</strong> exhibited approximately 27 times greater potency than 5F in HCT116 cells, with an IC<sub>50</sub> value of 0.232 μM. In an HCT116 xenograft mouse model, <strong>13</strong> displayed superior tumor inhibitory effects compared to fluorouracil (5-FU).</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118568"},"PeriodicalIF":3.0,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027912","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}
A serial of oxadiazol-2-ones/oxadiazole-2-thiones were designed, synthesized and evaluated as urease inhibitors. Out of these compounds, oxadiazole-2-thiones showed excellent inhibition against urease with twenty-two showing higher potency than the clinical used drug AHA. It is emphasized that 1,3,4-oxadiazole-2-thiones containing 3-propylphenoxy (d34) and 3-nitrophenoxy (d46) on the side chain were the two most active compounds. They were demonstrated having 230- and 360-fold higher potency than AHA and inhibiting urease with a mixed mechanism.
{"title":"Synthesis and evaluation of 5-phenoxylmethyl-1,3,4-oxadiazol-2-ones/oxadiazole-2-thiones as potent urease inhibitors.","authors":"Meng-Jing Xiao, Yi-Ning Wang, Liang-Chao Yuan, Yao Zeng, Zi-Wei Wu, Yun-Qi Zhang, Zhu-Ping Xiao, Hai-Liang Zhu","doi":"10.1016/j.bmc.2026.118567","DOIUrl":"https://doi.org/10.1016/j.bmc.2026.118567","url":null,"abstract":"<p><p>A serial of oxadiazol-2-ones/oxadiazole-2-thiones were designed, synthesized and evaluated as urease inhibitors. Out of these compounds, oxadiazole-2-thiones showed excellent inhibition against urease with twenty-two showing higher potency than the clinical used drug AHA. It is emphasized that 1,3,4-oxadiazole-2-thiones containing 3-propylphenoxy (d34) and 3-nitrophenoxy (d46) on the side chain were the two most active compounds. They were demonstrated having 230- and 360-fold higher potency than AHA and inhibiting urease with a mixed mechanism.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"118567"},"PeriodicalIF":3.0,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111788","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}
Pub Date : 2026-01-17DOI: 10.1016/j.bmc.2026.118573
Uriel Matthew Enriquez , Natalie M. González Velázquez , Mohammad Mosharraf Hossain , Jillian L. Kyzer , Ilia A. Guzei , Cody J. Wenthur
Antibodies against small psychoactive molecules have been developed for applications ranging from substance detection and overdose protection to mechanistic understanding of the actions of complex substance mixtures. In this study, we describe the design, synthesis, formulation, and animal testing of an initial immunogenic bioconjugate, as well as subsequent isolation of enantiospecific monoclonal antibodies against (2R,6R)-hydroxynorketamine, a putatively active metabolite of the dissociative-anesthetic and rapidly-acting antidepressant ketamine. Following pharmacophore synthesis, hapten generation was achieved through installation of 6-aminohexanoic acid linkers using reductive amination. Bioconjugation to the carrier protein, cross-reactive material 197 (CRM) was achieved via amide coupling. Upon administration to mice in combination with alum and CpG oligodeoxynucleotide 1826, (2R,6R)-hydroxynorketamine-CRM generated equivalent antibody titers to a comparator racemic 6-hydroxynorketamine-CRM hapten. Following creation of hybridomas arising from B-cells responsive to (2R,6R)-hydroxynorketamine-CRM exposure and subsequent screening, subcloning, sequencing, and production, we were able to identify a monoclonal antibody, 6F11-HC1-LC2, which yielded antibodies strongly responsive to (2R,6R)-hydroxynorketamine, but showed no responsiveness to (2S,6S)-hydroxynorketamine in a competitive binding enzyme-linked immunosorbent assay format. Surface plasmon resonance analysis of this monoclonal species demonstrated sub-nanomolar (0.4 nM) antibody affinity for (2R,6R)-hydroxynorketamine-BSA bioconjugates and > 150-fold selectivity in comparison to ketamine-BSA bioconjugates. Overall, these results demonstrate successful production of monoclonal antibodies capable of robustly distinguishing between hydroxynorketamine enantiomers, enabling their use in future in vivo studies to better understand their relative contributions to the rapidly-acting antidepressant properties of ketamine.
{"title":"Generation of enantiospecific monoclonal antibodies against (2R,6R)-hydroxynorketamine","authors":"Uriel Matthew Enriquez , Natalie M. González Velázquez , Mohammad Mosharraf Hossain , Jillian L. Kyzer , Ilia A. Guzei , Cody J. Wenthur","doi":"10.1016/j.bmc.2026.118573","DOIUrl":"10.1016/j.bmc.2026.118573","url":null,"abstract":"<div><div>Antibodies against small psychoactive molecules have been developed for applications ranging from substance detection and overdose protection to mechanistic understanding of the actions of complex substance mixtures. In this study, we describe the design, synthesis, formulation, and animal testing of an initial immunogenic bioconjugate, as well as subsequent isolation of enantiospecific monoclonal antibodies against (<em>2R,6R</em>)-hydroxynorketamine, a putatively active metabolite of the dissociative-anesthetic and rapidly-acting antidepressant ketamine. Following pharmacophore synthesis, hapten generation was achieved through installation of 6-aminohexanoic acid linkers using reductive amination. Bioconjugation to the carrier protein, cross-reactive material 197 (CRM) was achieved via amide coupling. Upon administration to mice in combination with alum and CpG oligodeoxynucleotide 1826, (<em>2R,6R</em>)-hydroxynorketamine-CRM generated equivalent antibody titers to a comparator racemic 6-hydroxynorketamine-CRM hapten. Following creation of hybridomas arising from B-cells responsive to (<em>2R,6R</em>)-hydroxynorketamine-CRM exposure and subsequent screening, subcloning, sequencing, and production, we were able to identify a monoclonal antibody, 6F11-HC<sub>1</sub>-LC<sub>2</sub>, which yielded antibodies strongly responsive to (<em>2R,6R</em>)-hydroxynorketamine, but showed no responsiveness to (<em>2S,6S</em>)-hydroxynorketamine in a competitive binding enzyme-linked immunosorbent assay format. Surface plasmon resonance analysis of this monoclonal species demonstrated sub-nanomolar (0.4 nM) antibody affinity for (<em>2R,6R</em>)-hydroxynorketamine-BSA bioconjugates and > 150-fold selectivity in comparison to ketamine-BSA bioconjugates. Overall, these results demonstrate successful production of monoclonal antibodies capable of robustly distinguishing between hydroxynorketamine enantiomers, enabling their use in future in vivo studies to better understand their relative contributions to the rapidly-acting antidepressant properties of ketamine.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118573"},"PeriodicalIF":3.0,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027902","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}
Pub Date : 2026-01-16DOI: 10.1016/j.bmc.2026.118570
Hsueh-Yun Lee , Chia-Hsuan Chang , Yi-Ting Liu , Deepa Rohidas Landge , Tzu-Ying Chen , Er-Chieh Cho
Colon cancer is one of the major causes of cancer-related death worldwide and is considered a consequence of the accumulation of genetic and epigenetic changes in normal cells. Among epigenetic modifications, the critical involvement of histone methyltransferase (HMT) in epigenetic alterations and tumorigenesis has been widely reported. Targeting HMTs as an anti-cancer strategy has attracted considerable attention; however, limited HMT inhibitors have achieved success in the field of clinical oncology.
In this study, we aimed to design and synthesize small molecular compounds as potential HMT inhibitors for cancer therapy, and to investigate their biological impacts on cancer cell lines. We examined the anti-proliferative effect of potential HMT inhibitors in multiple cancer cell lines. Among all candidates, two 1-benzylpiperidin-4-amine derivatives, DHT-07343 and DHT-07171, exhibited the most significant anti-cancer potential, especially in colon cancer cells. These two compounds could suppress methyltransferase activity, likely via regulating nuclear receptor-binding SET domain protein 1 (NSD1) and NSD2. In addition, these two compounds were able to inhibit cancer cell migration and regulate epithelial-mesenchymal transition (EMT) markers. Treatment of these two compounds led to apoptosis induction as well as cell cycle regulation. Finally, non-cancerous human cell lines and the zebrafish embryotoxicity model were utilized for the evaluation of the drug safety of DHT-07343 and DHT-07171.
In conclusion, our study demonstrated that DHT-07343 and DHT-07171 could be promising HMT inhibitors that exhibit anti-cancer activities by suppressing cell proliferation and migration, providing a potential strategy for colon cancer therapy.
{"title":"Targeting epithelial-mesenchymal transition and apoptosis: novel histone methyltransferase inhibitors for colon cancer suppression","authors":"Hsueh-Yun Lee , Chia-Hsuan Chang , Yi-Ting Liu , Deepa Rohidas Landge , Tzu-Ying Chen , Er-Chieh Cho","doi":"10.1016/j.bmc.2026.118570","DOIUrl":"10.1016/j.bmc.2026.118570","url":null,"abstract":"<div><div>Colon cancer is one of the major causes of cancer-related death worldwide and is considered a consequence of the accumulation of genetic and epigenetic changes in normal cells. Among epigenetic modifications, the critical involvement of histone methyltransferase (HMT) in epigenetic alterations and tumorigenesis has been widely reported. Targeting HMTs as an anti-cancer strategy has attracted considerable attention; however, limited HMT inhibitors have achieved success in the field of clinical oncology.</div><div>In this study, we aimed to design and synthesize small molecular compounds as potential HMT inhibitors for cancer therapy, and to investigate their biological impacts on cancer cell lines. We examined the anti-proliferative effect of potential HMT inhibitors in multiple cancer cell lines. Among all candidates, two 1-benzylpiperidin-4-amine derivatives, DHT-07343 and DHT-07171, exhibited the most significant anti-cancer potential, especially in colon cancer cells. These two compounds could suppress methyltransferase activity, likely via regulating nuclear receptor-binding SET domain protein 1 (NSD1) and NSD2. In addition, these two compounds were able to inhibit cancer cell migration and regulate epithelial-mesenchymal transition (EMT) markers. Treatment of these two compounds led to apoptosis induction as well as cell cycle regulation. Finally, non-cancerous human cell lines and the zebrafish embryotoxicity model were utilized for the evaluation of the drug safety of DHT-07343 and DHT-07171.</div><div>In conclusion, our study demonstrated that DHT-07343 and DHT-07171 could be promising HMT inhibitors that exhibit anti-cancer activities by suppressing cell proliferation and migration, providing a potential strategy for colon cancer therapy.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118570"},"PeriodicalIF":3.0,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035766","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}
Pub Date : 2026-01-16DOI: 10.1016/j.bmc.2026.118569
Mohammad M. Al-Sanea , Mohamed R. Elnagar , Ahmed A.B. Mohamed , Hamed W. El-Shafey , Lamiaa O. El-Halaby , Samar S. Tawfik , Susi Zara , Marwa Balaha , Abdullah A. Elgazar , Syed N.A. Bukhari , Abdelrahman Hamdi
This study reports the design, synthesis, and biological evaluation of thiazolidinedione (TZD) derivatives as dual inhibitors of α-amylase (α-AMY) and aldose reductase (AR) for potential use in the management of diabetes mellitus. Using a structure-based design strategy, the epalrestat scaffold was modified by introducing a TZD core with either an N-ethyl urea or N-acetamide linker and various benzylidene substituents. Two series of compounds (8a–g and 9a–g) were synthesized and characterized. In vitro assays showed that several derivatives exhibited dual inhibitory activity. Compound 9a, containing an N-acetamide linker and a 4-fluorobenzylidene group, inhibited AR (IC₅₀ = 117.6 nM) and α-AMY (IC₅₀ = 2.2 μM), with lower IC₅₀ values than epalrestat (127 nM) and acarbose (15 μM), respectively. Structure–activity relationship analysis indicated that the N-acetamide linker favored AR inhibition, whereas the N-ethyl urea linker was more favorable for α-AMY inhibition. Kinetic studies showed that 9a inhibits AR non-competitively and α-AMY via a mixed-type mechanism. Molecular docking suggested that 9a binds to an allosteric site in AR and the catalytic pocket of α-AMY. In a streptozotocin-induced diabetic mouse model, 9a reduced blood glucose levels by 68.4% at a dose of 50 mg/kg. These results suggest that 9a could serve as a starting point for further development of multi-target antidiabetic agents.
{"title":"Thiazolidinedione-based dual inhibitors of α-amylase and aldose reductase: Design, in vitro evaluation, and in vivo hypoglycemic activity","authors":"Mohammad M. Al-Sanea , Mohamed R. Elnagar , Ahmed A.B. Mohamed , Hamed W. El-Shafey , Lamiaa O. El-Halaby , Samar S. Tawfik , Susi Zara , Marwa Balaha , Abdullah A. Elgazar , Syed N.A. Bukhari , Abdelrahman Hamdi","doi":"10.1016/j.bmc.2026.118569","DOIUrl":"10.1016/j.bmc.2026.118569","url":null,"abstract":"<div><div>This study reports the design, synthesis, and biological evaluation of thiazolidinedione (TZD) derivatives as dual inhibitors of α-amylase (α-AMY) and aldose reductase (AR) for potential use in the management of diabetes mellitus. Using a structure-based design strategy, the epalrestat scaffold was modified by introducing a TZD core with either an <em>N</em>-ethyl urea or <em>N</em>-acetamide linker and various benzylidene substituents. Two series of compounds (<strong>8a–g</strong> and <strong>9a–g</strong>) were synthesized and characterized. <em>In vitro</em> assays showed that several derivatives exhibited dual inhibitory activity. Compound <strong>9a</strong>, containing an <em>N</em>-acetamide linker and a 4-fluorobenzylidene group, inhibited AR (IC₅₀ = 117.6 nM) and α-AMY (IC₅₀ = 2.2 μM), with lower IC₅₀ values than epalrestat (127 nM) and acarbose (15 μM), respectively. Structure–activity relationship analysis indicated that the <em>N</em>-acetamide linker favored AR inhibition, whereas the <em>N</em>-ethyl urea linker was more favorable for α-AMY inhibition. Kinetic studies showed that <strong>9a</strong> inhibits AR non-competitively and α-AMY <em>via</em> a mixed-type mechanism. Molecular docking suggested that <strong>9a</strong> binds to an allosteric site in AR and the catalytic pocket of α-AMY. In a streptozotocin-induced diabetic mouse model, <strong>9a</strong> reduced blood glucose levels by 68.4% at a dose of 50 mg/kg. These results suggest that <strong>9a</strong> could serve as a starting point for further development of multi-target antidiabetic agents.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118569"},"PeriodicalIF":3.0,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146016780","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}
Pub Date : 2026-01-16DOI: 10.1016/j.bmc.2026.118571
Lu Han , Shumin Zang , Wenxin Li , Hangtian Yue , Xiaoqian Zhou , Jie Chen , Meiyu Geng , Wenhu Duan , Zuoquan Xie , Zhengsheng Zhan
The adaptor molecule STING is embedded in the endoplasmic reticulum (ER) membrane. In innate immunity, STING is a critical cascade in regulating the cytoplasmic DNA-recognizing signaling. Aberrant STING signaling facilitates the host body to secrete an intolerable level of inflammatory cytokines as well as interferons, causing interferonopathies including STING-associated infantile vasculopathy, familial chilblain lupus, and amyotrophic lateral sclerosis. Suppressing the disordered STING signaling has demonstrated to ameliorate the inflammatory impairments of interferonopathy diseases. In this article, we provide the discovery of thieno[2,3-b][1,4]thiazin-2(3H)-one STING inhibitors. Through the structure-activity relationship (SAR) exploration, we identified compound 11 h as an oral-available STING inhibitor possessing cellular mouse- or human-STING inhibiting IC50 of 8.8 or 11.5 nM. Compound 11 h markedly hindered the cellular STING cascade in both murine- and human-derived cells. Furthermore, 11 h achieved robust in vivo activity opposing MAS-2-caused systemic inflammatory damage and cisplatin-caused renal inflammation and injury. Proposed binding model of 11 h-STING indicates that 11 h engages the transmembrane area of STING.
{"title":"Discovery of the thieno[2,3-b][1,4]thiazin-2(3H)-one STING inhibitors","authors":"Lu Han , Shumin Zang , Wenxin Li , Hangtian Yue , Xiaoqian Zhou , Jie Chen , Meiyu Geng , Wenhu Duan , Zuoquan Xie , Zhengsheng Zhan","doi":"10.1016/j.bmc.2026.118571","DOIUrl":"10.1016/j.bmc.2026.118571","url":null,"abstract":"<div><div>The adaptor molecule STING is embedded in the endoplasmic reticulum (ER) membrane. In innate immunity, STING is a critical cascade in regulating the cytoplasmic DNA-recognizing signaling. Aberrant STING signaling facilitates the host body to secrete an intolerable level of inflammatory cytokines as well as interferons, causing interferonopathies including STING-associated infantile vasculopathy, familial chilblain lupus, and amyotrophic lateral sclerosis. Suppressing the disordered STING signaling has demonstrated to ameliorate the inflammatory impairments of interferonopathy diseases. In this article, we provide the discovery of thieno[2,3-<em>b</em>][1,4]thiazin-2(3<em>H</em>)-one STING inhibitors. Through the structure-activity relationship (SAR) exploration, we identified compound <strong>11 h</strong> as an oral-available STING inhibitor possessing cellular mouse- or human-STING inhibiting IC<sub>50</sub> of 8.8 or 11.5 nM. Compound <strong>11 h</strong> markedly hindered the cellular STING cascade in both murine- and human-derived cells. Furthermore, <strong>11 h</strong> achieved robust <em>in vivo</em> activity opposing MAS-2-caused systemic inflammatory damage and cisplatin-caused renal inflammation and injury. Proposed binding model of <strong>11 h</strong>-STING indicates that <strong>11 h</strong> engages the transmembrane area of STING.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118571"},"PeriodicalIF":3.0,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146016718","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}
Pub Date : 2026-01-12DOI: 10.1016/j.bmc.2026.118555
Anastasiya S. Sokolova , Valeria V. Samsonova , Sergey O. Kuranov , Оlga I. Yarovaya , Artem D. Rogachev , Iana L. Esaulkova , Alexandrina S. Volobueva , Vladimir V. Zarubaev , Nariman F. Salakhutdinov
The persistent threat of influenza pandemics and the limitations of existing therapies necessitate the discovery of novel antiviral agents. This study investigates a series of monoterpenoid-based benzamides, derived from natural products (+)-camphor and (−)-fenchone, as a new class of inhibitors against influenza A virus (IAV). Building upon previous findings of their activity against orthopoxviruses, we identified several derivatives with potent activity against the A/H1N1 strain. Structure-activity relationship (SAR) analysis revealed that antiviral efficacy is critically dependent on the substituent's nature and position on the aromatic ring, the stereochemistry of the bicyclo[2.2.1]heptane core, and the amide configuration. Key lead compounds demonstrated significant inhibitory activity against the A/Puerto Rico/8/34 (H1N1) strain with high selectivity, and one derivative also showed promising activity against the highly pathogenic A(H7N9) strain. A representative compound demonstrated high metabolic stability in murine blood in vitro and exhibited promising pharmacokinetic properties in vivo following intragastric administration in mice. Mechanistic studies revealed two distinct profiles: one subset of inhibitors likely targets viral entry, while another appears to interfere with a later stage, such as assembly; their action is not mediated by neuraminidase inhibition. These findings establish monoterpenoid benzamides bearing the bicyclo[2.2.1]heptane motif as a promising scaffold for the development of anti-influenza agents, warranting further investigation into their precise molecular target and in vivo efficacy.
{"title":"Discovery of monoterpenoid-based benzamides bearing bicyclo[2.2.1]heptane motif as influenza H1N1 virus inhibitors","authors":"Anastasiya S. Sokolova , Valeria V. Samsonova , Sergey O. Kuranov , Оlga I. Yarovaya , Artem D. Rogachev , Iana L. Esaulkova , Alexandrina S. Volobueva , Vladimir V. Zarubaev , Nariman F. Salakhutdinov","doi":"10.1016/j.bmc.2026.118555","DOIUrl":"10.1016/j.bmc.2026.118555","url":null,"abstract":"<div><div>The persistent threat of influenza pandemics and the limitations of existing therapies necessitate the discovery of novel antiviral agents. This study investigates a series of monoterpenoid-based benzamides, derived from natural products (+)-camphor and (−)-fenchone, as a new class of inhibitors against influenza A virus (IAV). Building upon previous findings of their activity against orthopoxviruses, we identified several derivatives with potent activity against the A/H1N1 strain. Structure-activity relationship (SAR) analysis revealed that antiviral efficacy is critically dependent on the substituent's nature and position on the aromatic ring, the stereochemistry of the bicyclo[2.2.1]heptane core, and the amide configuration. Key lead compounds demonstrated significant inhibitory activity against the A/Puerto Rico/8/34 (H1N1) strain with high selectivity, and one derivative also showed promising activity against the highly pathogenic A(H7N9) strain. A representative compound demonstrated high metabolic stability in murine blood in vitro and exhibited promising pharmacokinetic properties in vivo following intragastric administration in mice. Mechanistic studies revealed two distinct profiles: one subset of inhibitors likely targets viral entry, while another appears to interfere with a later stage, such as assembly; their action is not mediated by neuraminidase inhibition. These findings establish monoterpenoid benzamides bearing the bicyclo[2.2.1]heptane motif as a promising scaffold for the development of anti-influenza agents, warranting further investigation into their precise molecular target and in vivo efficacy.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118555"},"PeriodicalIF":3.0,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145975840","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}
Pub Date : 2026-01-10DOI: 10.1016/j.bmc.2026.118552
Feifei Wang , Hongxue Dai , Kuanxin Wan , Mingliang Wang
CDK12 (Cyclin-dependent kinase 12) is a cyclin-dependent kinase that regulates gene transcription by phosphorylating the C-terminal domain of RNA polymerase II, playing a crucial role in maintaining genomic stability. Mutations or alterations in the CDK12 genome can trigger tumorigenesis and progression. Inhibiting the overexpression of CDK12 suppresses tumor growth and proliferation, indicating that it serves both as a biomarker for tumorigenesis and a potential therapeutic target for cancer treatment. In recent years, the structure and biological functions of CDK12 have been progressively elucidated, attracting significant research attention. Currently, the CDK12/13 inhibitor CT7439 is undergoing Phase I/II clinical trials. This paper provides a detailed review of various types of CDK12 small-molecule inhibitors/degraders, primarily based on key structural frameworks. It focuses on exploring the existing structure-activity relationships, aiming to offer a comprehensive perspective for developing highly selective CDK12-targeted inhibitors/degraders and providing valuable insights for future novel drug development.
{"title":"Therapeutic targeting of CDK12: a medicinal chemistry perspective","authors":"Feifei Wang , Hongxue Dai , Kuanxin Wan , Mingliang Wang","doi":"10.1016/j.bmc.2026.118552","DOIUrl":"10.1016/j.bmc.2026.118552","url":null,"abstract":"<div><div>CDK12 (Cyclin-dependent kinase 12) is a cyclin-dependent kinase that regulates gene transcription by phosphorylating the C-terminal domain of RNA polymerase II, playing a crucial role in maintaining genomic stability. Mutations or alterations in the CDK12 genome can trigger tumorigenesis and progression. Inhibiting the overexpression of CDK12 suppresses tumor growth and proliferation, indicating that it serves both as a biomarker for tumorigenesis and a potential therapeutic target for cancer treatment. In recent years, the structure and biological functions of CDK12 have been progressively elucidated, attracting significant research attention. Currently, the CDK12/13 inhibitor CT7439 is undergoing Phase I/II clinical trials. This paper provides a detailed review of various types of CDK12 small-molecule inhibitors/degraders, primarily based on key structural frameworks. It focuses on exploring the existing structure-activity relationships, aiming to offer a comprehensive perspective for developing highly selective CDK12-targeted inhibitors/degraders and providing valuable insights for future novel drug development.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118552"},"PeriodicalIF":3.0,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145975839","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}
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