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Design, Synthesis and Bio-Evaluation of Novel Chalcones Bridged with 1,3,4-Oxadiazole Linkers: ADMET and Docking Analysis
Chemistry & Biodiversity ( IF 2.3 ) Pub Date : 2022-11-23 , DOI: 10.1002/cbdv.202200681 Gopalarao Gogisetti 1, 2 , Umamaheswararao Kanna 1 , Vishal Sharma 2 , Tejeswara Rao Allaka 3 , Bhaskara Rao Tadiboina 1
Chemistry & Biodiversity ( IF 2.3 ) Pub Date : 2022-11-23 , DOI: 10.1002/cbdv.202200681 Gopalarao Gogisetti 1, 2 , Umamaheswararao Kanna 1 , Vishal Sharma 2 , Tejeswara Rao Allaka 3 , Bhaskara Rao Tadiboina 1
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In this article, we prepared a novel series of 1,3,4-oxadiazoles containing chalcone analogs via replacement of phthalazine which had increased antibacterial activity and the final compounds were confirmed by proton, carbon nuclear magnetic resonance spectroscopy, infrared and mass spectral analysis. Two sets of 1,3,4-oxadiazoles like 2-methyl-5-substitutedbenzylthio-1,3,4-oxadiazolyl-4-methylphthalazine-2-ones (3a–f), (E)-substituted phenyl acryloylphenyl-4-methyl-1-oxophthalazine-1,3,4-oxadiazolylthioacetamides (5a–f) were designed, synthesized and evaluated for their in vitro antibacterial potency against different Gram-(+ve), Gram-(–ve) microorganisms and fungal strains. The synthesized 4-methyl-2-{[5-({[2-(trifluoromethyl)phenyl]methyl}sulfanyl)-1,3,4-oxadiazol-2-yl]methyl}phthalazin-1(2H)-one (3c), 4-methyl-2-[(5-{[(4-nitrophenyl)methyl]sulfanyl}-1,3,4-oxadiazol-2-yl)methyl]phthalazin-1(2H)-one (3d), N-(4-{(2E)-3-[2-(dimethylamino)phenyl]prop-2-enoyl}phenyl)-2-({5-[(4-methyl-1-oxophthalazin-2(1H)-yl)methyl]-1,3,4-oxadiazol-2-yl}sulfanyl)acetamide (5d), and N-{4-[(2E)-3-(3-hydroxy-4-methoxyphenyl)prop-2-enoyl]phenyl}-2-({5-[(4-methyl-1-oxophthalazin-2(1H)-yl)methyl]-1,3,4-oxadiazol-2-yl}sulfanyl)acetamide (5e) displayed improved activity with MICs 1.41, 0.87, 2.16, 0.89 μg/mL as compared to the standard drugs rifamycin, ciprofloxacin, fluconazole (MIC=1.52, 1.94, 3.02 μg/mL). The prepared compounds were also analyzed with better target binding towards bacterial bioavailability, 5e exhibited highest bonds with amino acids ArgA45, LysA20, LysA17, ArgA171, AspA49, IleA14, HisA18 and having docking energy −8.68 Kcal/mol and dissociation constant 432.48 nM, respectively. These compounds were further evaluated for their ADMET and physicochemical properties by using SwissADME.
中文翻译：
与 1,3,4-恶二唑连接体桥接的新型查耳酮的设计、合成和生物评价：ADMET 和对接分析
在这篇文章中，我们通过取代酞嗪制备了一系列新的含有查尔酮类似物的 1,3,4-恶二唑类化合物，增强了抗菌活性，最终化合物通过质子、碳核磁共振光谱、红外和质谱分析得到证实。两组 1,3,4-恶二唑，如 2-methyl-5-substitutedbenzylthio-1,3,4-oxadiazolyl-4-methylphthalazine-2-ones ( 3a – f ), ( E )-substituted phenyl acryloylphenyl-4- methyl-1-oxophthalazine-1,3,4-oxadiazolylthioacetamides ( 5a – f) 被设计、合成并评估了它们对不同革兰氏 (+ve)、革兰氏 (–ve) 微生物和真菌菌株的体外抗菌效力。合成的 4-methyl-2-{[5-({[2-(trifluoromethyl)phenyl]methyl}sulfanyl)-1,3,4-oxadiazol-2-yl]methyl}phthalazin-1(2 H )-one ( 3c ), 4-methyl-2-[(5-{[(4-nitrophenyl)methyl]sulfanyl}-1,3,4-oxadiazol-2-yl)methyl]phthalazin-1(2 H )-one ( 3d ), N -(4-{(2 E )-3-[2-(二甲氨基)苯基]丙-2-烯酰}苯基)-2-({5-[(4-甲基-1-氧代酞嗪-2 (1 H )-基)甲基]-1,3,4-恶二唑-2-基}硫烷基)乙酰胺( 5d )，和N- {4-[(2 E)-3-(3-hydroxy-4-methoxyphenyl)prop-2-enyl]phenyl}-2-({5-[(4-methyl-1-oxophthalazin-2(1 H )-yl)methyl]-1 ,3,4-恶二唑-2-基}硫烷基）乙酰胺 ( 5e ) 与标准药物利福霉素、环丙沙星、氟康唑（MIC=1.52、1.94、 3.02 微克/毫升）。还分析了制备的化合物，其对细菌生物利用度具有更好的靶标结合，5e与氨基酸 ArgA 45、LysA 20、LysA 17、ArgA 171、AspA 49、IleA 14、HisA 18显示出最高的键合对接能分别为 −8.68 Kcal/mol 和解离常数 432.48 nM。使用 SwissADME 进一步评估了这些化合物的 ADMET 和理化性质。
更新日期：2022-11-23
中文翻译：
与 1,3,4-恶二唑连接体桥接的新型查耳酮的设计、合成和生物评价：ADMET 和对接分析
在这篇文章中，我们通过取代酞嗪制备了一系列新的含有查尔酮类似物的 1,3,4-恶二唑类化合物，增强了抗菌活性，最终化合物通过质子、碳核磁共振光谱、红外和质谱分析得到证实。两组 1,3,4-恶二唑，如 2-methyl-5-substitutedbenzylthio-1,3,4-oxadiazolyl-4-methylphthalazine-2-ones ( 3a – f ), ( E )-substituted phenyl acryloylphenyl-4- methyl-1-oxophthalazine-1,3,4-oxadiazolylthioacetamides ( 5a – f) 被设计、合成并评估了它们对不同革兰氏 (+ve)、革兰氏 (–ve) 微生物和真菌菌株的体外抗菌效力。合成的 4-methyl-2-{[5-({[2-(trifluoromethyl)phenyl]methyl}sulfanyl)-1,3,4-oxadiazol-2-yl]methyl}phthalazin-1(2 H )-one ( 3c ), 4-methyl-2-[(5-{[(4-nitrophenyl)methyl]sulfanyl}-1,3,4-oxadiazol-2-yl)methyl]phthalazin-1(2 H )-one ( 3d ), N -(4-{(2 E )-3-[2-(二甲氨基)苯基]丙-2-烯酰}苯基)-2-({5-[(4-甲基-1-氧代酞嗪-2 (1 H )-基)甲基]-1,3,4-恶二唑-2-基}硫烷基)乙酰胺( 5d )，和N- {4-[(2 E)-3-(3-hydroxy-4-methoxyphenyl)prop-2-enyl]phenyl}-2-({5-[(4-methyl-1-oxophthalazin-2(1 H )-yl)methyl]-1 ,3,4-恶二唑-2-基}硫烷基）乙酰胺 ( 5e ) 与标准药物利福霉素、环丙沙星、氟康唑（MIC=1.52、1.94、 3.02 微克/毫升）。还分析了制备的化合物，其对细菌生物利用度具有更好的靶标结合，5e与氨基酸 ArgA 45、LysA 20、LysA 17、ArgA 171、AspA 49、IleA 14、HisA 18显示出最高的键合对接能分别为 −8.68 Kcal/mol 和解离常数 432.48 nM。使用 SwissADME 进一步评估了这些化合物的 ADMET 和理化性质。
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