Medicinal Chemistry Research最新文献_第8页

Design, synthesis and evaluation of imidazo[1,2-a]pyrazin-8(7H)-one derivatives as acetylcholinesterase inhibitors and antioxidants 咪唑并[1,2-a]吡嗪-8(7H)-酮衍生物作为乙酰胆碱酯酶抑制剂和抗氧化剂的设计、合成与评估

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-08-24 DOI: 10.1007/s00044-024-03298-w

Wen-Rong Du, Ben-Ben Wei, Xin-Yuan Guo, Yong Lan, Pan-Pan Shang, Yi-Xuan Wang, Xue-Wei Zhou, Xiao-Ke Wang, Zheng-Yue Ma

{"title":"Design, synthesis and evaluation of imidazo[1,2-a]pyrazin-8(7H)-one derivatives as acetylcholinesterase inhibitors and antioxidants","authors":"Wen-Rong Du, Ben-Ben Wei, Xin-Yuan Guo, Yong Lan, Pan-Pan Shang, Yi-Xuan Wang, Xue-Wei Zhou, Xiao-Ke Wang, Zheng-Yue Ma","doi":"10.1007/s00044-024-03298-w","DOIUrl":"10.1007/s00044-024-03298-w","url":null,"abstract":"<div><p>A series of 8-(piperazin-1-yl)imidazo[<i>1,2-a</i>]pyrazine derivatives were designed and synthesized as acetylcholinesterase inhibitors (AChEIs) and antioxidants for the treatment of Alzheimer’s disease (AD). Moreover, the biological evaluation results demonstrated that these synthesized compounds exhibited moderate inhibitory activities toward acetylcholinesterase (AChE) and radical scavenging activities. Among them, compound <b>17r</b> was the most potent AChE inhibitor with an IC<sub>50</sub> value of 0.47 μM and moderate inhibitory activity against butyrylcholinesterase (BuChE) (IC<sub>50</sub> = 11.02 μM). The selectivity index (SI) value of AChE over BuChE was 23.45, surpassing that of the reference drug galantamine (AChE IC<sub>50</sub> = 5.01 μM, BuChE IC<sub>50</sub> = 18.46 μM, SI = 3.68). Compound <b>17o</b> had the best antioxidant activity with an IC<sub>50</sub> value of 89.33 μM, which was lower than that of ascorbic acid (IC<sub>50</sub> value = 25.70 μM) as the control drug. Furthermore, the results of molecular docking studies indicated that <b>17r</b> could simultaneously bind to both catalytic active site and peripheral anionic site of AChE, which was consistent with the mixed inhibition pattern shown by enzyme kinetic studies. The interaction’s stability of <b>17r</b>-AChE/BuChE were also assessed using a conventional atomistic 100 ns dynamics simulation study, which revealed the conformational stability of representative compound <b>17r</b> in the cavity of the AChE. In addition, the molecular properties of all compounds were predicted online through the SwissADME, and the best active compound <b>17r</b> matched the properties of most orally administered drugs. Based on the biological activity and molecular properties, compound <b>17r</b> as AChEI was valuable for further development.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 10","pages":"1938 - 1953"},"PeriodicalIF":2.6,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142181073","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}

引用次数: 0

Anticancer potential of delphinidin and its derivatives: therapeutic and mechanistic insights 德尔菲尼丁及其衍生物的抗癌潜力：治疗和机理见解

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-08-14 DOI: 10.1007/s00044-024-03296-y

Shabnoor Iqbal, Timothy Omara, Ivan Kahwa, Usman Mir Khan

{"title":"Anticancer potential of delphinidin and its derivatives: therapeutic and mechanistic insights","authors":"Shabnoor Iqbal, Timothy Omara, Ivan Kahwa, Usman Mir Khan","doi":"10.1007/s00044-024-03296-y","DOIUrl":"10.1007/s00044-024-03296-y","url":null,"abstract":"<div><p>Anthocyanins are water-soluble naturally occurring flavonoids present in fruits, flowers, leaves, and roots of fruit plants and vegetables. One of the important anthocyanidin components of red wine and berries is delphinidin (DP). This review provides an update on the potential of DP in cancer therapy, with a further understanding of the mechanisms involved. Delphinidin has been shown to elicit inhibitory effects on catabolizing enzymes of human granulocytes and parasites, TNF-induced COX-2 expression in mouse epidermal cells, and reduce oxidative stress. It also inhibited anchorage-independent growth and caused cell death in breast cancer cell lines. Delphinidin increased Nrf2 expression, increased HO-1 production, and promoted mRNA expression of mitochondrial biogenesis-related factors. Further, DP has anti-proliferative and pro-apoptotic effects in various cancer cell lines such as lung, breast, and ovarian cancer cells. The mTOR-related pathway is the most important signaling pathway in the activation of autophagy, and DP has been shown to exert its cytotoxic effects on cancer cell lines via activating protein kinases. Among DP derivatives, delphinidin-3-O-glucoside has the best anticancer activity because it is easily absorbed. However, the metabolism of DP and its bioavailability in biological systems need to be explored to fully understand its benefits.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 10","pages":"1769 - 1786"},"PeriodicalIF":2.6,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-024-03296-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142181075","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}

引用次数: 0

Terrein: Isolation, synthesis, and upscaling of a functional scaffold for multifaceted biomedical applications Terrein：用于多方面生物医学应用的功能性支架的分离、合成和放大

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-08-10 DOI: 10.1007/s00044-024-03294-0

Vaishali Raghuvanshi, Diksha Katiyar

引用次数: 0

Dauricine: a review of natural observation, pharmacology, and pharmacokinetics 杜冷丁：自然观察、药理学和药代动力学综述

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-08-09 DOI: 10.1007/s00044-024-03297-x

Tran Quang Hai, Nguyen Thi Huong, Ninh The Son

{"title":"Dauricine: a review of natural observation, pharmacology, and pharmacokinetics","authors":"Tran Quang Hai, Nguyen Thi Huong, Ninh The Son","doi":"10.1007/s00044-024-03297-x","DOIUrl":"10.1007/s00044-024-03297-x","url":null,"abstract":"<div><p><i>Menispermum dauricum</i> DC (the moonseed family Menispermaceae) was used to treat various diseases, such as inflammatory disorders, and arrhythmia. Dauricine (DRC) is the principal bisbenzylisoquinoline alkaloid found in the roots of this medicinal plant. To date, there is still a lack of documents that review natural occurrence, and pharmacological and pharmacokinetic studies regarding this molecule. The current research tends to fill this gap. References have been systematically searched from the Web’s largest databases, such as Web of Science, Google Scholar, Sci-Finder, PubMed, and others, for relevant literature. The current review has also covered the pharmacological processes and mechanisms of the studied compound in a visible arrangement. DRC has possessed a great variety of in vitro and in vivo pharmacological activities, including anticancer, anti-inflammatory, and vasorelaxant, as well as protection to the brain, bone, and lungs. The underlying mechanisms relate to various signaling pathways, in which the NF-κB (nuclear factor kappa B) can be seen as the main route. Pharmacokinetic actions of DRC may relate to the loss of proton and methyl groups, and/or the addition of hydroxyl and sugar units, whereas its absolute bioavailability is found to be less than 50%. The other pharmacological assays are expected. More studies mentioning clinical experiments, toxicology, and bioavailability are encouraged. Structural modification is such a good approach to enhance pharmacological value and reduce toxicity</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 10","pages":"1787 - 1803"},"PeriodicalIF":2.6,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141924652","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}

引用次数: 0

Design, synthesis and biological evaluation of potent thiazolidinedione salicylic acid inhibitors against glyoxalase-I as potential anticancer agents 作为潜在抗癌剂的强效噻唑烷二酮水杨酸抑制剂乙二醛酶-I 的设计、合成和生物学评价

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-08-09 DOI: 10.1007/s00044-024-03247-7

Banan O. Alomari, Lara I. Fakhouri, Nizar A. Al‑Shar’i, Qosay Albalas

{"title":"Design, synthesis and biological evaluation of potent thiazolidinedione salicylic acid inhibitors against glyoxalase-I as potential anticancer agents","authors":"Banan O. Alomari, Lara I. Fakhouri, Nizar A. Al‑Shar’i, Qosay Albalas","doi":"10.1007/s00044-024-03247-7","DOIUrl":"10.1007/s00044-024-03247-7","url":null,"abstract":"<div><p>The worldwide rise in cancer incidence and mortality rates has spurred the search for new pathways implicated in cancer development and progression. One such target is glyoxalase 1 (GLO-I), a key player in methylglyoxal detoxification and a factor in the proliferation and prognosis of numerous cancers. Recent studies led by Al-Shar’i et al. utilized computer-aided drug design to identify potential inhibitors of GLO-I. The second most potent hit, (<i>Z</i>)-5-(5-((2,4-dioxothiazolidin-5-ylidene)methyl)furan-2-yl)-2-hydroxybenzoic acid, (IC<sub><i>50</i></sub> = 4.24 µM), was selected as a lead for further optimization. Through molecular docking, 27 analogs were designed and evaluated for binding affinity, with 14 of the top-scorings synthesized and tested for their inhibitory activity against GLO-I. The majority of these analogs showed enhanced activities relative to the lead compound, with the most potent having an IC<sub>50</sub> of 150 nM. These findings pave the way for the continued development of highly effective GLO-I inhibitors.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 9","pages":"1526 - 1540"},"PeriodicalIF":2.6,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141933191","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}

引用次数: 0

Novel monastrol/melatonin hybrids as a new approach for colorectal cancer intervention: design, synthesis, biological activity, and drug-likeness modeling studies 作为结直肠癌干预新方法的新型甲萘醌/褪黑素混合物：设计、合成、生物活性和药物相似性模型研究

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-08-08 DOI: 10.1007/s00044-024-03223-1

David Preciado-A, Andrés F. Yepes, Angie Herrera-R, Wilson Cardona-G

{"title":"Novel monastrol/melatonin hybrids as a new approach for colorectal cancer intervention: design, synthesis, biological activity, and drug-likeness modeling studies","authors":"David Preciado-A, Andrés F. Yepes, Angie Herrera-R, Wilson Cardona-G","doi":"10.1007/s00044-024-03223-1","DOIUrl":"10.1007/s00044-024-03223-1","url":null,"abstract":"<div><p>Considering the important increase in the incidence and mortality of colorectal cancer, it is necessary to develop new strategies in the search for new alternatives against this disease. Hence, we designed and synthesized a new series of monastrol/melatonin hybrids and evaluated them in vitro and in silico to determine the potential of these new chemical entities on this type of cancer. To achieve this goal, the different compounds were evaluated in human colorectal adenocarcinoma cells SW480, while establishing the selective potential of the hybrids through the nonmalignant human colon mucosal epithelial cell line (NCM460). According to the results, hybrids <b>6a</b>, <b>6c</b>, <b>6i</b>, and <b>6j</b> displayed the best response, with IC<sub>50</sub> values in the range of 5.2 and 6.3 μM, inducing important changes depending on concentration and time. In addition, these compounds were extremely active in comparison to the single molecules, and they were slightly more selective than the reference drug (5 fluorouracil, 5-FU). Besides, an optimal pharmacokinetic and toxicological profile was also estimated for hybrids <b>6a</b>, <b>6c</b>, <b>6i</b>, and <b>6j</b>. Altogether, novel hybrids of monastrol-MLT, in particular, <b>6a</b> (-H), <b>6c</b> (3-OMe), <b>6i</b> (3,4-OMe), and <b>6j</b> (3,5-OMe) could be addressed as starting points for further pharmacological studies concerning to combat colorectal cancer.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 9","pages":"1511 - 1525"},"PeriodicalIF":2.6,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-024-03223-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141926624","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}

引用次数: 0

Contrasting effect of different crowding agents on pseudoknot RNA stability 不同拥挤剂对假结 RNA 稳定性的对比效应

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-08-08 DOI: 10.1007/s00044-024-03293-1

Sagar Satpathi, T. Endoh, Naoki Sugimoto

引用次数: 0

Further exploration of N-4 substituents on the piperazine ring of the hybrid template 5/ 7-{[2-(4-Aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol and its analog: development of an exceptionally potent agonist for D2 & D3 receptors 进一步探索混合模板 5/ 7-{[2-(4-芳基-哌嗪-1-基)-乙基]-丙基-氨基}-5,6,7,8-四氢-2-萘酚及其类似物的哌嗪环上的 N-4 取代基：开发出 D2 和 D3 受体的特效激动剂

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-08-08 DOI: 10.1007/s00044-024-03291-3

Aloke K. Dutta, Banibrata Das, Asawari Lote, Tamara Antonio, Maarten Reith

{"title":"Further exploration of N-4 substituents on the piperazine ring of the hybrid template 5/ 7-{[2-(4-Aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol and its analog: development of an exceptionally potent agonist for D2 & D3 receptors","authors":"Aloke K. Dutta, Banibrata Das, Asawari Lote, Tamara Antonio, Maarten Reith","doi":"10.1007/s00044-024-03291-3","DOIUrl":"10.1007/s00044-024-03291-3","url":null,"abstract":"<div><p>In this manuscript we report a structure-activity relationship (SAR) study of analogs of 5/ 7-{[2-(4-Aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol. Our study is focused on introduction of various bioisoteric and aromatic substitutions on the piperazine ring of the hybrid template to further probe into the accessory binding domains on dopamine D<sub>2</sub>/D<sub>3</sub> receptors. Specifically, the goal behind this study is to delineate the nature of the binding pockets for such substitutions on the piperazine ring to determine their influence on binding affinity (Ki), as measured with tritiated spiperone and HEK-293 cells expressing either D<sub>2</sub> or D<sub>3</sub> receptors. Functional activity of selected compounds was assessed with the GTPγS binding assay. Our data indicates that various N-substitution with substituted and unsubstituted benzene sulfonyl group produced varied affinity and potency for D<sub>2</sub>/D<sub>3</sub>. Compound <b>D-660</b> produced highest selectivity for the D<sub>3</sub> receptor in the binding assay. In general, presence of hydroxyl group improved overall activity for both D<sub>2</sub>/D<sub>3</sub> receptors. One such compound <b>D-668</b> produced exceptional potencies for both the receptors. Overall, our results suggest that binding to the sites removed from the orthosteric binding sites contribute significantly to enhance functional potencies of ligands.</p><div><figure><div><div><picture><img></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 12","pages":"2420 - 2430"},"PeriodicalIF":2.6,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141929459","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}

引用次数: 0

Exploration of potential antihypertensive peptides derived from farmed Chinese giant salamander (Andrias davidianus) 从养殖的中国大鲵中提取的潜在抗高血压肽的探索

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-08-08 DOI: 10.1007/s00044-024-03292-2

Chi-Wei Lee, Christoper Caesar Yudho Sutopo, Jong-Yuan Lee, Yu-Kuo Chen, Jue-Liang Hsu

{"title":"Exploration of potential antihypertensive peptides derived from farmed Chinese giant salamander (Andrias davidianus)","authors":"Chi-Wei Lee, Christoper Caesar Yudho Sutopo, Jong-Yuan Lee, Yu-Kuo Chen, Jue-Liang Hsu","doi":"10.1007/s00044-024-03292-2","DOIUrl":"10.1007/s00044-024-03292-2","url":null,"abstract":"<div><p>The alcalase digestate of farmed Chinese giant salamander meat powder (FCGSMP) demonstrated antihypertensive properties through inhibition of angiotensin-I-converting enzyme (ACE), with an ACE IC<sub>50</sub> value of 22.8 ± 1.8 µg/mL. Initiated by a zwitterionic hydrophilic interaction liquid chromatography solid-phase extraction (ZIC HILIC-SPE) fractionation, FCGSMP alcalase hydrolysate was fractionated, and fraction H1 from the ZIC HILIC-SPE fractionation showed the highest angiotensin-I-converting enzyme inhibitory (ACEI) activity (ACE IC<sub>50</sub> = 21.3 ± 0.2 µg/mL). Fraction H1 from the ZIC HILIC-SPE fractionation was further separated using a reversed-phase C<sub>18</sub> solid-phase extraction (RP-SPE). Fraction S2 from the RP-SPE fractionation exhibited the highest ACEI activity (ACE IC<sub>50</sub> = 7.7 ± 0.2 µg/mL) among the six RP-SPE fractions. Using synthetic peptides, twenty identified peptides from fraction S2 were confirmed to have ACEI activity. The ACE IC<sub>50</sub> values of the four most potent ACEI peptides (LLPGW, PLYE, KLW, and LGEW) were calculated to be 9.1 ± 0.1, 67.2 ± 1.5, 92.5 ± 2.9, and 98.2 ± 4.7 µM, respectively. LLGPW (LW5) exhibited the strongest ACEI activity compared to the others. Furthermore, the study of its inhibitory mechanism using the Lineweaver-Burk plot suggested that LW5 acts as a competitive inhibitor. Molecular docking simulation of LW5 with human tACE (1O8A.pdb) indicated that LW5 can form interactions with the ACE catalytic site. Subsequently, LW5 was categorized as an ACE true-inhibitor type and remained unaltered during simulated gastrointestinal digestion. To the best of our knowledge, this is the first report of exploration into angiotensin-I-converting enzyme inhibitory peptides derived from farmed Chinese giant salamander meat.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 10","pages":"1914 - 1925"},"PeriodicalIF":2.6,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141925951","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}

引用次数: 0

Novel 2-[(8-hydroxyquinolin-7-yl)(phenyl)methylamino]benzoic acid analogs targeting the active site of botulinum neurotoxins: designing, synthesis, and biological evaluation 针对肉毒杆菌神经毒素活性位点的新型 2-[(8-羟基喹啉-7-基)(苯基)甲氨基]苯甲酸类似物：设计、合成和生物学评价

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-08-03 DOI: 10.1007/s00044-024-03272-6

Surabhi Agnihotri, Vinita Chauhan Kushwah, Surabhi Bansal, Manorama Vimal, Nandita Saxena, Ram Kumar Dhaked

{"title":"Novel 2-[(8-hydroxyquinolin-7-yl)(phenyl)methylamino]benzoic acid analogs targeting the active site of botulinum neurotoxins: designing, synthesis, and biological evaluation","authors":"Surabhi Agnihotri, Vinita Chauhan Kushwah, Surabhi Bansal, Manorama Vimal, Nandita Saxena, Ram Kumar Dhaked","doi":"10.1007/s00044-024-03272-6","DOIUrl":"10.1007/s00044-024-03272-6","url":null,"abstract":"<div><p>Botulinum neurotoxins are the most lethal and category ‘A’ bioterrorism agent. Despite all efforts, there is no drug available for intoxicating human. The 8-HQ is a well-known privileged scaffold which possesses metal chelation properties and its derived compounds are reported to inhibit the catalytic activity of BoNTs. Novel derivatives of NSC1012 were designed and synthesized via Mannich reaction. After characterization by NMR & mass spectrometry, compounds were studied for its toxicity profiling by in vitro and in vivo experiments. The designed compounds were screened and validated against BoNTs using molecular docking and FTS assay. The derived derivatives displayed no significant hemolytic activity (upto 500 µM) and low cytotoxicity with the CC<sub>50</sub> value ranging from 105.94–80.97 µM. The in vivo assay reveals, 25 mM concentration is a NOAEL dose with no observed significant difference in biochemical parameters between the control and treated groups. Molecular docking study showed “hits” with the binding energies for BoNT/A found in the range of −11.65 to −7.24 kcal/mol, BoNT/B between −10.69 to −6.91 kcal/mol, BoNT/E it was −8.18 to −5.30 kcal/mol and for BoNT/F were −8.94 to −6.86 kcal/mol. The FTSA result reveals the binding efficiency of the compounds with the shift in <i>ΔT</i><sub><i>m</i></sub> from 8.10 to −7.15 °C for serotypes under study. Synthesized compounds are less toxic to the cells, not significantly affect the biochemical profile of the animals, and have shown high binding affinity as well as inhibited the catalytic activity of the BoNTs. These molecules can pave the way for the development of therapeutics against the neurotoxins.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 9","pages":"1625 - 1642"},"PeriodicalIF":2.6,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141885811","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}

引用次数: 0