Abid Aisha, Lateef Mehreen, Rafiq Naushaba, Eijaz Sana, Tauseef Saima
Department of Chemistry, University of Karachi, Karachi 75270, Pakistan.
Department of Chemistry, University of Karachi, Karachi 75270, Pakistan.
Biomed Pharmacother. 2022 Feb;146:112561. doi: 10.1016/j.biopha.2021.112561. Epub 2021 Dec 26.
Herein, we report a comparative study based on structure, thermal and solution stability, and biopotency against lipoxygenase (LOX), butyrylcholinesterase (BChE) and microbes for Pd(II) compounds of N,O,S bearing 5-(CHXR)-1,3,4-oxadiazole-2-thiones (L') of type [PdL'Cl] (P'n) and N,O bearing respective hydrazides (L) of type trans-[PdLCl] (Pn) {X = C, R = 4-I, 2-Br, 4-NO, 3-NO, 2-Cl, 3-Cl (n = 1-6, serially); X = N (n = 7)}. Spectral techniques (IR, EI-MS, NMR) and physicochemical evaluations successfully characterized the new compounds. The L' behaved as bidentate S-N donors bonded through exocyclic sulfur and N-3' nitrogen, while L acted as amino N donors. UV-vis (solution speciation) and thermal degradation profiles consistently confirmed the greater stability for P'n than Pn compounds. These compounds manifested varying degree in vitro potential to inhibit LOX, BChE and several bacteria and fungi, affected mainly by Pd(II) presence, M-L binding mode, nature and position of R, or halo groups electronegativity. Molecular docking with human 5-LOX and BChE further validated the respective experimental inhibition findings and explored several putative mechanistic interactions (H-bonding, π-stacking, π-alkyl, π-S, etc.) at the enzyme active sites. Pn generally offered superior antimicrobial and anti-LOX (anti-inflammatory) potential than respective P'n compounds, with P3/P'5, P(2,3,7)/P'3, and P6 being comparable, better and equivalent to ampicillin, nystatin and baicalein, the reference antibacterial, antifungal and anti-LOX drugs, respectively. Contrarily, the anti-BChE activity of P'n was found better than Pn compounds, showing P'2/P1 as the most promising anti-Alzheimer drug candidates. This study bares important structural and mechanistic aspects in optimizing antimicrobial, anti-inflammatory and anti-Alzheimer activities, highlighting some potential future pallado-drug candidates.
在此，我们报告了一项对比研究，该研究基于结构、热稳定性和溶液稳定性，以及针对脂氧合酶（LOX）、丁酰胆碱酯酶（BChE）和微生物的生物活性，研究对象为[PdL'Cl]（P'n）型含N、O、S的5-(CHXR)-1,3,4-恶二唑-2-硫酮（L'）和反式-[PdLCl]（Pn）型含相应酰肼（L）的钯（II）化合物{X = C，R = 4-I、2-Br、4-NO、3-NO、2-Cl、3-Cl（n = 1 - 6，依次排列）；X = N（n = 7）}。光谱技术（红外光谱、电子轰击质谱、核磁共振）和物理化学评估成功地表征了这些新化合物。L'作为双齿S - N供体，通过环外硫和N - 3'氮键合，而L作为氨基N供体。紫外可见光谱（溶液形态分析）和热降解曲线一致证实P'n化合物比Pn化合物具有更高的稳定性。这些化合物在体外表现出不同程度的抑制LOX、BChE以及多种细菌和真菌的潜力，主要受钯（II）的存在、M - L结合模式、R的性质和位置或卤素基团电负性的影响。与人类5 - LOX和BChE的分子对接进一步验证了各自的实验抑制结果，并探索了在酶活性位点的几种假定的机制相互作用（氢键、π堆积、π - 烷基、π - S等）。一般来说，Pn比相应的P'n化合物具有更强的抗菌和抗LOX（抗炎）潜力，其中P3/P'5、P(2,3,7)/P'3和P6分别与参考抗菌、抗真菌和抗LOX药物氨苄西林、制霉菌素和黄芩苷相当、更好和等效。相反，发现P'n的抗BChE活性优于Pn化合物，其中P'2/P1是最有前景的抗阿尔茨海默病药物候选物。这项研究揭示了在优化抗菌、抗炎和抗阿尔茨海默病活性方面重要的结构和机制方面，突出了一些潜在的未来钯药物候选物。
