{"title":"Design of novel benzimidazole-propane hydrazide derivatives as α-glucosidase and α-amylase inhibitors: in vitro and in silico studies","authors":"Shiva Mohammadizadeh, Somaye Karimian, Navid Dastyafteh, Milad Noori, Fatemeh Doraghi, Maryam Mohammadi-Khanaposhtani, Bagher Larijani, Mohammad Mahdavi, Nastaran Sadeghian, Aydın Aktaş, Parham Taslimi, İlhami Gulçin","doi":"10.1007/s00044-024-03328-7","DOIUrl":"10.1007/s00044-024-03328-7","url":null,"abstract":"<div><p>A new series of benzimidazole-propane hydrazide derivatives <b>9a-k</b> were designed, synthesized, and evaluated for their inhibition ability against α-glucosidase and α-amylase. The results of the in vitro evaluations showed that all the tested compounds exhibited significant inhibition against α-glucosidase and α-amylase. Title compounds <b>9a-k</b> exhibited varying degrees of inhibitory ability against α-glucosidase, with IC<sub>50</sub> values in the range of 73.86–151.54 nM, in comparison to the standard acarbose drug with IC<sub>50</sub> value of 174.50 nM. Similarly, these compounds demonstrated varying degrees of α-amylase inhibitory ability (the IC<sub>50</sub> values ranged from 42.50 to 78.58 nM in comparison to acarbose with IC<sub>50</sub> of 79.05 nM). Among the synthesized compounds, compound <b>9</b> <b>h</b> demonstrated the highest α-glucosidase inhibitory activity and compound <b>9</b> <b>f</b> demonstrated the highest anti-α-amylase activity. To further investigation on the potential of these derivatives as α-glucosidase and α-amylase inhibitors, molecular docking were conducted on all the synthesized compounds <b>9a-k</b>. Docking results were in agreement with in vitro results. Molecular dynamics of compound <b>9</b> <b>h</b> showed that complex compound <b>9h-</b>α-glucosidase had acceptable stability and flexibility. Calculations of physicochemical properties of compound <b>9a-k</b> showed that these compounds fallowed of the main drug-likeness rules. Furthermore, the prediction of pharmacokinetics and toxicity profiles of compound <b>9</b> <b>h</b> showed that this compound can be considered as a lead drug structure.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 1","pages":"205 - 218"},"PeriodicalIF":2.6,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912862","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, synthesis and investigating the in vitro and in silico HDAC8 inhibitory activities of derivatives of [6]-shogaol and [6]-gingerol isolated from ginger (Zingiber officinale)","authors":"Thitiporn Kamloon, Pattamabhorn Worsawat, Chanokbhorn Phaosiri, Chiwarat Romsanthia, Puttima Pimphoklang, La-or Somsakeesit, Thanaset Senawong, Gulsiri Senawong, Narissara Namwan, Nopawit Khamto, Puracheth Rithchumpon, Pakit Kumboonma","doi":"10.1007/s00044-024-03337-6","DOIUrl":"10.1007/s00044-024-03337-6","url":null,"abstract":"<div><p>The main components, [6]-shogaol (<b>6</b>) and [6]-gingerol (<b>7</b>), were obtained from the rhizome of <i>Zingiber officinale</i>. Both natural phenolic compounds were modified at C<sub>4′</sub> position to get new sixteen derivatives. All derivatives were screened for their HDAC inhibitory activity at 50 µM using HeLa nuclear extract. Among the synthesized compounds, derivatives <b>6b</b>, <b>6e</b>, <b>6f</b> and <b>6g</b> were the most effective against HDACs with the IC<sub>50</sub> values as 44.60 ± 1.40 µM, 49.23 ± 1.13 µM, 50.55 ± 4.25 µM and 48.52 ± 1.52 µM, respectively. In addition, the selected derivatives were investigated against HDAC8 inhibitory activity. The results demonstrated that among them, <b>6b</b> was selective with HDAC8 (IC<sub>50</sub> = 23.19 ± 1.57 µM). The molecular docking study via MOE docking program also revealed that compound <b>6b</b> bound into the active pocket of HDAC8 with Δ<i>G</i> value as −6.92 kcal/mol. Moreover, the in vitro antiproliferative activity of four most potent compounds were evaluated against nine cancer cell lines with MTT assay. The results showed that all selected derivatives were most effective against lung (A549), colon (HCT116 and HT29) and human cervical (HeLa) cancer cell lines. Especially, compound <b>6g</b> was the most potent against A549 cancer cell line with the IC<sub>50</sub> value as 8.41 ± 0.04 µM. Therefore, compound <b>6b</b> and <b>6g</b> are considered as promising HDACs-inhibitor-anticancer agents.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 1","pages":"272 - 284"},"PeriodicalIF":2.6,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912807","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":"Naturally occurring organosulfur for treating metabolic disorders and infectious diseases","authors":"Gautam Kumar","doi":"10.1007/s00044-024-03326-9","DOIUrl":"10.1007/s00044-024-03326-9","url":null,"abstract":"<div><p>Sulfur has been used as a medicinal agent by the Greeks since ancient times. Approximately 350 sulfur-containing compounds have been approved as drugs by the Food and Drug Administration (FDA). Generally, sulfur exists as organosulfur in plants and as glucosinolates and isothiocyanates. Metabolic disorders and infectious diseases are becoming worldwide public health problems, directly affecting individuals' quality of life and constitute a robust economic challenge to healthcare systems. Glucosinolates have been reported in several vegetables, bacteria, plants, fungi, and animals. In addition to organosulfur, glucosinolates, and their hydrolyzed products, isothiocyanates have immense therapeutic value. Several studies suggest glucosinolates have a potential role in treating metabolic disorders, including cancer, diabetes, and inflammation. Also, some of the glucosinolates had shown broad-spectrum antimicrobial activity against gram-positive and gram-negative bacteria and antifungal activity against fungal strains. This review discusses recently identified naturally occurring sulfur-containing compounds, including glucosinolates and organosulfur, and their therapeutic potential for treating metabolic disorders and infectious diseases.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 1","pages":"45 - 85"},"PeriodicalIF":2.6,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912757","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}
Aya Y. Rashad, Hoda G. Daabees, Mohamed Elagawany, Mohamed Shahin, Ahmed E. Abdel Moneim, Maram Y. Marei, Sherif A. F. Rostom
{"title":"Dual inhibition strategy addressing hyperuricemia and oxidative stress: design, biological evaluation and stability studies of febuxostat-probenecid mutual prodrug","authors":"Aya Y. Rashad, Hoda G. Daabees, Mohamed Elagawany, Mohamed Shahin, Ahmed E. Abdel Moneim, Maram Y. Marei, Sherif A. F. Rostom","doi":"10.1007/s00044-024-03317-w","DOIUrl":"10.1007/s00044-024-03317-w","url":null,"abstract":"<div><p>The mutual prodrug approach appears as a promising strategy for developing candidates with great therapeutic effectiveness and enhanced safety profile. The present study addresses the assessment of merging the xanthine oxidase (XO) inhibitor febuxostat (FEB) with the URAT1 inhibitor probenecid (PRO) for managing hyperuricemia and gout associated with oxidative stress. Accordingly, FEB-PRO <b>(5)</b> prodrug was synthesized and proved to be a significant hypouricemic and free radical scavenging agent, when compared to its parents and the physical mixture. Moreover, <b>(5)</b> was found to remarkably decrease serum and hepatic XO as compared with the parent drugs and physical mixture. Inclusion of PRO imparted synergism and enhancement of the pharmacological profile of FEB. Additionally, the tested prodrug showed protective effect against hepatotoxicity caused by carbon tetrachloride, beside being non cytotoxic to normal breast cells. Also, RT-PCR analysis showed that the expression of antioxidant biomarkers CAT and SOD2 significantly increased in the group treated with FEB-PRO <b>(5)</b>. Being an ester, <b>(5)</b> displayed reduced aqueous solubility and increased lipophilicity relative to the parent medications.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 12","pages":"2476 - 2490"},"PeriodicalIF":2.6,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826264","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}
Mamdouh F. A. Mohamed, Ahmed M. Soliman, Omar Alshazly, Ayman Nafady, Razium Ali Soomro
{"title":"Design, synthesis, molecular docking, and antibacterial activity of novel amide-linked tetrahydrobenzothienopyrimidinone derivatives as potential DNA gyrase and topoisomerase IV inhibitors","authors":"Mamdouh F. A. Mohamed, Ahmed M. Soliman, Omar Alshazly, Ayman Nafady, Razium Ali Soomro","doi":"10.1007/s00044-024-03325-w","DOIUrl":"10.1007/s00044-024-03325-w","url":null,"abstract":"<div><p>A series of tetrahydrobenzo [4, 5] thieno [2, 3-<i>d</i>] pyrimidinone derivatives <b>3a</b>–<b>j</b> and <b>4</b>–<b>6</b> was synthesized, and tested for their inhibitory activity against <i>E. coli</i> DNA gyrase in a supercoiling assay. The results showed that the five most promising compounds, <b>3d</b>, <b>3g</b>, <b>3h</b>, <b>3i</b> and <b>3j</b> were the most potent, therefore, they were selected for investigating their inhibitory activity against <i>E. coli</i> topoisomerase IV, <i>S. aureus</i> DNA gyrase, and <i>S. aureus</i> topoisomerase IV. The results revealed that compound <b>3j</b> was a more effective inhibitor of <i>E. coli</i> topoisomerase IV, <i>S. aureus</i> DNA gyrase and <i>S. aureus</i> topoisomerase IV, respectively. The molecular docking study of compound <b>3j</b> has revealed that it binds effectively in the active sites of <i>E. coli</i> DNA gyrase B and <i>E. coli</i> DNA topoisomerase. The hybrid <b>3j</b> particularly showed promise as a scaffold for designing and developing novel therapeutic antibacterial candidates.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 1","pages":"172 - 182"},"PeriodicalIF":2.6,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912754","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":"Shaping the future of medicine through diverse therapeutic applications of tetralin derivatives","authors":"Bhumi M. Shah, Radhika N. Kachhadiya","doi":"10.1007/s00044-024-03331-y","DOIUrl":"10.1007/s00044-024-03331-y","url":null,"abstract":"<div><p>Tetralin is an ortho-fused bicyclic hydrocarbon notable for its odour of a mixture of benzene and menthol and high boiling point. Its low vapor pressure has limited its study by far-infrared spectroscopy but vibrational data have been obtained through alternative methods such as single vibronic level fluorescence (SVLF) and high-temperature vapor-phase Raman spectra. Tetralin is of more than chemical interest because it is part of several biologically active compounds. Interestingly, tetralin is a structural element of the anthracycline antibiotics that are clinically applied in cancer chemotherapy owing to their DNA-intercalating activity. The tetralin ring is crucial in sertraline, an antidepressant, and other clinically relevant compounds, including antifungal, anti-Parkinsonian, and anti-inflammatory activity. A comprehensive overview of tetralin derivatives with their diverse biological activities and therapeutic potentials has been discussed in the review. It also encompasses the synthetic methodology for the synthesis of tetralin and its derivatives including hydrogenation, and cyclization through metal catalysts, and visible light. In addition, a green chemical synthetic technique such as supercritical fluid technology was discussed, which improves the production of tetralin. Apart from that, metabolic pathways and catabolism of tetralin in biological systems and drug delivery systems of tetralin have been discussed. The review underlines the importance of tetralin derivatives in medicinal chemistry and has future developmental potential in therapeutic applications.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 1","pages":"86 - 113"},"PeriodicalIF":2.6,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912753","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}
Esra Basaran, Fatma Gizem Avci, Aslihan Ozcan, Ceyda Kula, Soumaya Ben Ali Hassine, Ozlem Keskin, Pemra Ozbek, Berna Sariyar Akbulut
{"title":"Antivirulence therapy: type IV pilus as a druggable target for bacterial infections","authors":"Esra Basaran, Fatma Gizem Avci, Aslihan Ozcan, Ceyda Kula, Soumaya Ben Ali Hassine, Ozlem Keskin, Pemra Ozbek, Berna Sariyar Akbulut","doi":"10.1007/s00044-024-03338-5","DOIUrl":"10.1007/s00044-024-03338-5","url":null,"abstract":"<div><p>Virulence is an organism’s ability to infect the host and cause disease, and this ability is determined by the presence of virulence factors. The “do not kill, neutralize” strategy used by antivirulence therapies is a novel approach to managing the increasing drug resistance. In this respect, type IV pilus is one druggable target among many virulence factors. The type IV pili (T4P) assembly systems with adaptable and flexible filaments are utilized by numerous pathogens for infection. The current work focuses on druggable targets of T4aP with specific emphasis on <i>Pseudomonas aeruginosa</i>, <i>Neisseria meningitidis</i>, and <i>Neisseria gonorrhoeae</i>. Additionally, available information on potential inhibitor molecules that attenuate T4P activities or impair pilus function and/or assembly in different pathogens is summarized. The structural organization of T4aP suggests that ATPases, pilins, tip-associated adhesins, and peptidases could be considered potential target sites. As the number of high-resolution structures of different T4P systems and the computational power to model T4P machineries increase, the pace in the identification of novel molecules and targets to attenuate the activities of T4P will accelerate. Artificial intelligence, which has already penetrated into our daily lives, will definitely have a prominent role in providing a framework for progress in this area.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 2","pages":"285 - 300"},"PeriodicalIF":2.6,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925469","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, synthesis, and evaluation of antitumor activity of quinazoline derivatives containing different terminal segments of basic amine groups","authors":"Shihao Wang, Zichen Yang, Dongling Gu, JiaHui Han, Hongjing Chen, Hao Wang, JiaXin Zheng, Hongmin Liu, Yu Ke, Qiurong Zhang","doi":"10.1007/s00044-024-03320-1","DOIUrl":"10.1007/s00044-024-03320-1","url":null,"abstract":"<div><p>In this study, we designed and synthesized 41 quinazoline derivatives with different base amine termini. Compound <b>15n</b> showed the best antiproliferation activity against A549 cells with IC<sub>50</sub> value of 1.91 μM in four cancer cell lines (MGC-803, PC-3, A549, and Eca-109). In colony, scratch, and apoptosis experiments, compound <b>15n</b> inhibited proliferation, migration, and apoptosis of A549 cells in a concentration-dependent manner and blocked the cell cycle in the G0/G1 phase. Overall, our study suggests that compound <b>15n</b> has potential as a lead compound for the development of antitumor drugs.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 1","pages":"134 - 153"},"PeriodicalIF":2.6,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913056","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":"Synthesis and in vitro antiproliferative evaluation of novel drimane oxepinyl triazoles from labdane diterpene sclareol","authors":"Gulzar Hussain, Manzoor Ahmed, Sundas Chowdhary, Sanket K. Shukla, Syed Khalid Yousuf","doi":"10.1007/s00044-024-03334-9","DOIUrl":"10.1007/s00044-024-03334-9","url":null,"abstract":"<div><p>A series of new oxepinyl triazoles were synthesized using labdane diterpene sclareol as a template. The synthesis process involved several steps including oxidation, oxetane ring opening, deacetylation, tosylation, and azidation followed by Huisgen’s 1,3-dipolar cycloaddition reaction with different alkynes. The newly synthesized compounds were confirmed using <sup>1</sup>H NMR and <sup>13</sup>C NMR. These novel drimane oxepinyl triazoles derived from labdane diterpene sclareol were evaluated for their antiproliferative efficacy in colon (HCT-116), breast (MCF-7), and lung (A-549) cancer cell lines. Compound <b>14m</b> demonstrated significant cytotoxic effects in all tested cell lines with an IC<sub>50</sub> of 16 µM. Initial investigations suggested that the compound induced apoptosis and inhibited cancer cell proliferation, indicating the potential of drimane oxepinyl triazoles as promising therapeutic agents for various cancers.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 1","pages":"240 - 251"},"PeriodicalIF":2.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912780","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}
Juan Zhang, Conghao Gai, Jing Wang, Xiaobin Zhuo, Yan Zou, Jishun Yang, Yan Song, Qingjie Zhao, Xiaoyun Chai
{"title":"Synthesis of the dibenzylbutane lignan LCA derivatives and evaluation of their anti-inflammatory activities","authors":"Juan Zhang, Conghao Gai, Jing Wang, Xiaobin Zhuo, Yan Zou, Jishun Yang, Yan Song, Qingjie Zhao, Xiaoyun Chai","doi":"10.1007/s00044-024-03332-x","DOIUrl":"10.1007/s00044-024-03332-x","url":null,"abstract":"<div><p>The roots of <i>Litsea cubeba</i> (Lour.) Pers have been used for the treatment of rheumatism. We previously extracted and isolated the natural product dibenzylbutane lignan LCA with anti-inflammatory activity. In the current study, using LCA as the lead compound, two series of LCA derivatives with an imide structure and butadiene structure were designed and synthesized. Among them, compounds <b>10c</b> and <b>16a</b> showed stronger inhibitory effects on LPS-induced NO and ROS production in RAW264.7 cells. Further study showed that compound <b>16a</b> not only reduced the levels of inflammatory cytokines, including IL-6, TNF-α, and IL-1β, but it also significantly reduced the expression of iNOS and COX-2. Preliminary mechanism of action studies suggested that <b>16a</b> exerts anti-inflammatory effects by inhibiting the NF-κB signaling pathway. Overall, our results suggest that compound <b>16a</b> may be used as a promising anti-inflammatory drug to enrich the compound library. Further study into compound <b>16a</b> could provide research ideas and methods for developing anti-inflammatory drugs.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 1","pages":"228 - 239"},"PeriodicalIF":2.6,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912864","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}