Kandrakonda Yelamanda Rao, Remya Chandran, K V Dileep, Sri Charitha Gorantla, Shaik Jeelan Basha, Sreelakshmi Mothukuru, Irla Siva Kumar, Katta Vamsi, Sandeep Kumar, Aramati Bindu Madhava Reddy, Rajagopal Subramanyam, Amooru Gangaiah Damu
{"title":"喹唑啉酮-肼基氰乙酰胺混合物作为强效多靶点定向药物治疗阿尔茨海默病:设计、合成以及生化、硅学和机理分析。","authors":"Kandrakonda Yelamanda Rao, Remya Chandran, K V Dileep, Sri Charitha Gorantla, Shaik Jeelan Basha, Sreelakshmi Mothukuru, Irla Siva Kumar, Katta Vamsi, Sandeep Kumar, Aramati Bindu Madhava Reddy, Rajagopal Subramanyam, Amooru Gangaiah Damu","doi":"10.1021/acschemneuro.4c00424","DOIUrl":null,"url":null,"abstract":"<p><p>The discovery of effective multitarget-directed ligands (MTDLs) against multifactorial Alzheimer's disease (AD) remnants has been focused in an incessant drug discovery pursuit. In this perception, the current study explores the rational design, synthesis, and evaluation of 26 quinazolinone-hydrazine cyanoacetamide hybrids <b>7(a-j)</b>, <b>8(a-j)</b>, and <b>9(a-f)</b> as MTDLs against AD. These new compounds were synthesized in four-step processes using simple phthalimide as the starting material without any major workup procedures and were characterized by different spectroscopic techniques. In Ellman's assay, the most potent analogues <b>7i</b>, <b>8j</b>, and <b>9d</b> were identified as selective and mixed-type inhibitors of hAChE. Furthermore, biophysical and computational assessments revealed that the analogues <b>7i</b>, <b>8j</b>, and <b>9d</b> were bound to both the catalytic active site and peripheral anionic site of hAChE with high affinity. The molecular dynamics simulation analysis highlighted the conformational changes of hAChE upon binding of <b>7i</b>, <b>8j</b>, and <b>9d</b> and also the stability of resulting biomolecular systems all over 100 ns simulations. In addition to antioxidant activity, the most active congeners were found to protect substantially SK-N-SH cells from oxidative damage. Decisively, the most active analogues <b>7i</b>, <b>8j</b>, and <b>9d</b> were assessed as potent Aβ<sub>1-42</sub> fibril modulators and protective agents against Aβ<sub>1-42</sub>-induced toxicity in SH-SY5Y cells. Additionally, glioblastoma C6 cell-based assays also demonstrated the use of the most active congeners <b>7i</b>, <b>8j</b>, and <b>9d</b> as protective agents against Aβ<sub>1-42</sub>-induced toxicity. Overall, this multifunctional capacity of quinazolinone-hydrazine cyanoacetamide hybrids demonstrated the noteworthy potential of these hybrids to develop as effectual MTDLs against AD. However, further pharmacokinetics, toxicology, and behavioral studies are warranted.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"3401-3420"},"PeriodicalIF":4.1000,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Quinazolinone-Hydrazine Cyanoacetamide Hybrids as Potent Multitarget-Directed Druggable Therapeutics against Alzheimer's Disease: Design, Synthesis, and Biochemical, In Silico, and Mechanistic Analyses.\",\"authors\":\"Kandrakonda Yelamanda Rao, Remya Chandran, K V Dileep, Sri Charitha Gorantla, Shaik Jeelan Basha, Sreelakshmi Mothukuru, Irla Siva Kumar, Katta Vamsi, Sandeep Kumar, Aramati Bindu Madhava Reddy, Rajagopal Subramanyam, Amooru Gangaiah Damu\",\"doi\":\"10.1021/acschemneuro.4c00424\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The discovery of effective multitarget-directed ligands (MTDLs) against multifactorial Alzheimer's disease (AD) remnants has been focused in an incessant drug discovery pursuit. In this perception, the current study explores the rational design, synthesis, and evaluation of 26 quinazolinone-hydrazine cyanoacetamide hybrids <b>7(a-j)</b>, <b>8(a-j)</b>, and <b>9(a-f)</b> as MTDLs against AD. These new compounds were synthesized in four-step processes using simple phthalimide as the starting material without any major workup procedures and were characterized by different spectroscopic techniques. In Ellman's assay, the most potent analogues <b>7i</b>, <b>8j</b>, and <b>9d</b> were identified as selective and mixed-type inhibitors of hAChE. Furthermore, biophysical and computational assessments revealed that the analogues <b>7i</b>, <b>8j</b>, and <b>9d</b> were bound to both the catalytic active site and peripheral anionic site of hAChE with high affinity. The molecular dynamics simulation analysis highlighted the conformational changes of hAChE upon binding of <b>7i</b>, <b>8j</b>, and <b>9d</b> and also the stability of resulting biomolecular systems all over 100 ns simulations. In addition to antioxidant activity, the most active congeners were found to protect substantially SK-N-SH cells from oxidative damage. Decisively, the most active analogues <b>7i</b>, <b>8j</b>, and <b>9d</b> were assessed as potent Aβ<sub>1-42</sub> fibril modulators and protective agents against Aβ<sub>1-42</sub>-induced toxicity in SH-SY5Y cells. Additionally, glioblastoma C6 cell-based assays also demonstrated the use of the most active congeners <b>7i</b>, <b>8j</b>, and <b>9d</b> as protective agents against Aβ<sub>1-42</sub>-induced toxicity. Overall, this multifunctional capacity of quinazolinone-hydrazine cyanoacetamide hybrids demonstrated the noteworthy potential of these hybrids to develop as effectual MTDLs against AD. 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Quinazolinone-Hydrazine Cyanoacetamide Hybrids as Potent Multitarget-Directed Druggable Therapeutics against Alzheimer's Disease: Design, Synthesis, and Biochemical, In Silico, and Mechanistic Analyses.
The discovery of effective multitarget-directed ligands (MTDLs) against multifactorial Alzheimer's disease (AD) remnants has been focused in an incessant drug discovery pursuit. In this perception, the current study explores the rational design, synthesis, and evaluation of 26 quinazolinone-hydrazine cyanoacetamide hybrids 7(a-j), 8(a-j), and 9(a-f) as MTDLs against AD. These new compounds were synthesized in four-step processes using simple phthalimide as the starting material without any major workup procedures and were characterized by different spectroscopic techniques. In Ellman's assay, the most potent analogues 7i, 8j, and 9d were identified as selective and mixed-type inhibitors of hAChE. Furthermore, biophysical and computational assessments revealed that the analogues 7i, 8j, and 9d were bound to both the catalytic active site and peripheral anionic site of hAChE with high affinity. The molecular dynamics simulation analysis highlighted the conformational changes of hAChE upon binding of 7i, 8j, and 9d and also the stability of resulting biomolecular systems all over 100 ns simulations. In addition to antioxidant activity, the most active congeners were found to protect substantially SK-N-SH cells from oxidative damage. Decisively, the most active analogues 7i, 8j, and 9d were assessed as potent Aβ1-42 fibril modulators and protective agents against Aβ1-42-induced toxicity in SH-SY5Y cells. Additionally, glioblastoma C6 cell-based assays also demonstrated the use of the most active congeners 7i, 8j, and 9d as protective agents against Aβ1-42-induced toxicity. Overall, this multifunctional capacity of quinazolinone-hydrazine cyanoacetamide hybrids demonstrated the noteworthy potential of these hybrids to develop as effectual MTDLs against AD. However, further pharmacokinetics, toxicology, and behavioral studies are warranted.
期刊介绍:
ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following:
Neurotransmitters and receptors
Neuropharmaceuticals and therapeutics
Neural development—Plasticity, and degeneration
Chemical, physical, and computational methods in neuroscience
Neuronal diseases—basis, detection, and treatment
Mechanism of aging, learning, memory and behavior
Pain and sensory processing
Neurotoxins
Neuroscience-inspired bioengineering
Development of methods in chemical neurobiology
Neuroimaging agents and technologies
Animal models for central nervous system diseases
Behavioral research