Department of Chemistry, Integral University, Lucknow, UP 226026, India.
Department of Biochemistry, Era's Lucknow Medical College & Hospital, Sarfarazganj, Hardoi Road, Lucknow, UP 226003, India.
Curr Comput Aided Drug Des. 2021;17(1):107-122. doi: 10.2174/1573409915666190926122103.
Mixed ligand-metal complexes are efficient chelating agents because of their flexible donor ability. Mixed ligand complexes containing hetero atoms sulphur, nitrogen and oxygen have been probed for their biological significance.
Nine mixed ligand-metal complexes of 2-(butan-2-ylidene) hydrazinecarbothioamide (2- butanone thiosemicarbazone) with pyridine, bipyridine and 2-picoline as co-ligands were synthesized with Cu, Co and Zn salts. The complexes were tested against MDA-MB231 (MDA) and A549 cell lines. Antibacterial activity was tested against Staphylococcus aureus and Escherichia coli. The drug character of the complexes was evaluated on parameters viz. physicochemical properties, bioactivity scores, toxicity assessment and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) profile using various automated softwares. Molecular docking was performed against Ribonucleotide Reductase (RR) and topoisomerase II (topo II).
The mixed ligand-metal complexes were synthesized by condensation reaction for 4-5 h. The characterization was done by elemental analysis, 1H-NMR, FT-IR, molar conductance and UV spectroscopic techniques. Molecular docking results showed that [Cu(CHNS)(py)2(CH3COO)2], [Zn(CHNS)(bpy)(SO)] and [Zn(CHNS)(2-pic)2(SO4)] displayed the lowest binding energies with respect to RR. Against topo II [Cu(CHNS)(py)2(CH3COO)2], [Cu(CHNS)(bpy)(CH3COO)2] and [Zn(CHNS)(2-pic)2(SO)] had the lowest energies. The druglikness assessment was done using Leadlikeness and Lipinski's rules. Not more than two violations were obtained in case of each filtering rule showing drug-like character of the mixed ligand complexes. Some of the complexes exhibited positive bioactivity scores and almost all the complexes were predicted to be safe with no hazardous effects as predicted by the toxicity assessment. Ames test predicted the non-mutagenic nature of the complexes.
In vitro activity evaluation showed that [Zn(CHNS)(py)2(SO)], [Co(CHNS(bpy) (Cl)2] and [Cu(CHNS)(2-pic)2(CH3COO)2] were active against MDA. Against A549 [Co(CHNS)(py)2(Cl)2], [Cu(CHNS)(py)2(CH3COO)2] and [Co(CHNS(bpy)(Cl)2] were active. Antibacterial evaluation showed that [Co(CHNS)(bpy)(Cl)2], [Zn(CHNS)(2-pic)2(SO)] and [Cu(CHNS)(2-pic)2(CH3COO)2] were active against S. aureus. Against E. coli, [Zn(CHNS)(2- pic)2(SO)] showed activity at 18-20 mg dose range.
混合配体金属配合物因其灵活的供体能力而成为有效的螯合剂。含有硫、氮和氧等杂原子的混合配体配合物已被研究用于其生物学意义。
用吡啶、联吡啶和 2-吡啶甲酰胺作为共配体，与 Cu、Co 和 Zn 盐合成了 9 种 2-（丁-2-亚基）肼甲硫酰胺（2-丁酮缩硫代氨基脲）的混合配体金属配合物。将这些配合物用于 MDA-MB231（MDA）和 A549 细胞系进行测试。对抗菌活性进行了测试，对抗金黄色葡萄球菌和大肠杆菌。使用各种自动化软件，根据理化性质、生物活性评分、毒性评估以及吸收、分布、代谢、排泄和毒性（ADMET）特征，对配合物的药物特性进行了评估。利用核糖核苷酸还原酶（RR）和拓扑异构酶 II（topo II）进行了分子对接。
通过缩合反应 4-5 小时合成了混合配体金属配合物。通过元素分析、1H-NMR、FT-IR、摩尔电导率和紫外光谱技术进行了表征。分子对接结果表明，[Cu（CHNS）（py）2（CH3COO）2]、[Zn（CHNS）（bpy）（SO）]和[Zn（CHNS）（2-pic）2（SO4）]与 RR 结合的最低结合能。在 topo II 中，[Cu（CHNS）（py）2（CH3COO）2]、[Cu（CHNS）（bpy）（CH3COO）2]和[Zn（CHNS）（2-pic）2（SO）]具有最低的能量。利用 Leadlikeness 和 Lipinski 规则进行了药物相似性评估。每个过滤规则的结果都不超过两个违规，表明混合配体配合物具有药物特征。一些配合物表现出阳性的生物活性评分，几乎所有的配合物都被预测为安全的，没有毒性评估预测的危险影响。Ames 试验预测了配合物的非致突变性质。
体外活性评价表明，[Zn（CHNS）（py）2（SO）]、[Co（CHNS（bpy）（Cl）2]和[Cu（CHNS）（2-pic）2（CH3COO）2]对 MDA 具有活性。对 A549，[Co（CHNS）（py）2（Cl）2]、[Cu（CHNS）（py）2（CH3COO）2]和[Co（CHNS（bpy）（Cl）2]具有活性。抗菌评价表明，[Co（CHNS）（bpy）（Cl）2]、[Zn（CHNS）（2-pic）2（SO）]和[Cu（CHNS）（2-pic）2（CH3COO）2]对金黄色葡萄球菌有活性。对大肠杆菌，[Zn（CHNS）（2-pic）2（SO）]在 18-20mg 剂量范围内显示出活性。
