The compounds 2a-2h containing a thiazolidinone pharmacophore were synthesized via hetrerocylization of thiosemicarbazones with dimethyl acetylenedicarboxylate. The hybrid molecules were evaluated for anticancer activity against the human cell lines MCF-7, T47D (human breast adenocarcinoma) and HeLa (cervical cancer). Compounds 2c showed effective cytotoxicity on MCF-7 and HeLa (GI50 6.40 ± 0.10 μM/mL and GI5010.30 ± 1.09 μM/mL), and compound 2d also showed effective cytotoxicity against MCF-7 and HeLa cell lines i.e., (GI50 16.60 ± 0.21 μM/mL and GI50 15.02 ± 0.14 μM/mL). These findings were comparable to cisplatin (azane;dichloroplatinum) the standard drug (GI50 13.20 ± μM/mL and 15.10 μM/mL respectively) and consequently nominated for determination of the mode of cell death. The results revealed the cytotoxic effects of 2c and 2d by induction of apoptosis in MCF-7 and HeLa cell lines. Moreover the results were further supported by the Molecular Docking which predicts the binding interactions of the best anticancer ligands with Ribonucleotide reductase (RNR), which is essential enzyme required for de-novo synthesis of DNA precursors. Molecular dynamic simulations were also performed to determine the stability of protein-ligand complex under different simulated conditions. In addition, the computational studies including DFTs, ADMET properties suggested these compounds can act as lead molecules, for the synthesis of novel drug candidates for the treatment of specific cancer and its associated malignancies.
In present study, Water Quality Index (WQI) has been assessed of the Rawal Lake which is a major source of drinking water for people in the Federal Capital, Islamabad, and its adjacent city Rawalpindi in Pakistan. For this, the principal component analysis (PCA) and WQI were applied as an integrated approach to quantitatively explore difference based on spatial variation in 11 water quality parameters of the five major feeding tributaries of the Rawal Lake, Pakistan. The results of temperature in water, total dissolved solids, pH, electrical conductivity, chlorides and sulfates were well within the allowable World Health Organisation's (WHO) limits. However, the heavy metals like cadmium and lead were above permissible limits by the WHO in tributaries of Bari Imam and Rumli. Moreover, this has been proven by the Pearson correlation which suggested strong positive correlation (0.910*) between lead and cadmium. The results of present study were subjected to statistical analysis, i.e., PCA which gave three major factors contributing 96.5% of the total variance. For factor 1, pH, TDS, alkalinity, chlorides, sulfates and zinc have highest factor loading values (>0.60) and presented that these parameters were among the most significant parameters of first factor. As per the WQI results, the water was categorised in two major classes indicating that water of Bari Imam and Rumli is highly contaminated with heavy metals and totally unsuitable for drinking purposes. Based on the results of the present study, it is suggested to make heavy metals consideration as an integrated component in future planning for maintaining water quality of the Rawal Lake and its tributaries.
Atherosclerosis is a leading cause of death worldwide. The adverse side effects of currently available drugs urge to find more effective and safe remedial agents. Alternative candidates from natural resources are of great consequence in the emerging of new drugs. Pandanus tectorius (Pandanaceae) was traditionally used in Ayurvedic medicine to cure certain diseases. Thus, the current study conducted to elucidate the potency of P. tectorius fruit as antiatherosclerosis and antihypercholesterolemia agents through the regulation of high density lipoprotein (HDL) receptor (scavenger receptor [SR]-B1) gene expression and 3-hydroxy-3-methylglutaryl coenzyme A reductase reductase (HMGCR) in vitro, respectively. The P. tectorius fruit was noncytotoxic against the HepG2 cell line confirmed by 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl tetrazolium bromide assay. The P. tectorius fruit successfully upregulates the SR-B1 gene expression and downregulate the HMGCR. Moreover, anin vivo study showed that P. tectorius has good activity on the upregulation of HDL and subsequently downregulation of total cholesterol level. Moreover, P. tectorius fruit did not show any increase in toxicity biomarkers serum glutamic oxaloacetic transaminase and serum glutamate pyruvate transaminase in vivo. These results found that P. tectorius fruits have potency as the preventive agent for hypercholesterolemia and atherosclerosis via SR-B1 and HMGCR mechanisms of action.
The bidentate N-(1-Alkylpyridin-4(1H)-ylidene)amide (PYA) pro-ligands [H2LBn][Cl]2 (2), and [H2LMe][TfO]2 (3) were prepared by simple alkylation reactions of the known compound, N,N-di(pyridin-4-yl)oxalamide (H2L, 1). The Pd(II) complexes, [Pd(LBn)2][Cl]2 (4), [Pd(LMe)2][Cl][TfO] (5), Pd(LBn)Cl2 (6) and Pd(LMe)Cl2 (7) were synthesized through reactions between these pro-ligands and suitable Pd(II) substrates in the presence of base. The molecular structures of 3 and 6 were obtained by single crystal X-ray structure determinations. Studies of the experimental and computational DNA binding interactions of the compounds 1-7 revealed that overall 4 and 6 have the largest values for the binding parameters Kb and ΔGbo. The results showed a good correlation with the steric and electronic parameters obtained by quantitative structure activity relationship (QSAR) studies. In-vitro cytotoxicity studies against four different cell lines showed that the human breast cancer cell lines MCF-7, T47D and cervical cancer cell line HeLa had either higher or similar sensitivities towards 4, 6 and 2, respectively, compared to cisplatin. In general, the cytotoxicity of the compounds, represented by IC50 values, decreased in the order 4 > 6 > 2 > 5 > 3 > 1 > 7 in cancer cell lines. Apoptosis contributed significantly to the cytotoxic effects of these anticancer agents as evaluated by apoptosis studies.
In the present work, a concise library of 1,3,5-triaryl-2-pyrazolines (2a-2q) was designed and synthesized by employing a multistep strategy, and the newly synthesized compounds were screened for their urease and α-glucosidase inhibitory activities. The compounds (2a-2q) were characterized using a combination of several spectroscopic techniques including FT-IR, 1H NMR, 13C NMR, and EI-MS. All the synthesized compounds, except compound 2i, were potent against urease as compared to the standard inhibitor thiourea (IC50 = 21.37 ± 0.26 μM). These analogs disclosed varying degrees of urease inhibitory activities ranging from 9.13 ± 0.25 to 18.42 ± 0.42 μM. Compounds 2b, 2g, 2m, and 2q having IC50 values of 9.36 ± 0.27, 9.13 ± 0.25, 9.18 ± 0.35, and 9.35 ± 0.35 μM, respectively, showed excellent inhibitory activity as compared to standard thiourea (IC50 = 21.37 ± 0.26 μM). A kinetic study of compound 2g revealed that compound 2g inhibited urease in a competitive mode. Among the synthesized pyrazolines, the compounds 2c, 2k, 2m, and 2o exhibited excellent α-glucosidase inhibitory activity with the lowest IC50 values of 212.52 ± 1.31, 237.26 ± 1.28, 138.35 ± 1.32, and 114.57 ± 1.35 μM, respectively, as compared to the standard acarbose (IC50 = 375.82 ± 1.76 μM). The compounds (2a-2q) showed α-glucosidase IC50 values in the range of 114.57 ± 1.35 to 462.94 ± 1.23 μM. Structure-activity relationship revealed that the size and electron-donating or -withdrawing effects of substituents influenced the activities, which led to the urease and α-glucosidase inhibiting properties. Compound 2m was a dual potent inhibitor against urease and α-glucosidase due to the presence of 2-CF3 electron-withdrawing functionality on the phenyl ring. To the best of our knowledge, these synthetic compounds were found to be the most potent dual inhibitors of urease and α-glucosidase with minimum IC50 values. The cytotoxicity of the compounds (2a-2q) was also investigated against human cell lines MCF-7 and HeLa. Compound 2l showed moderate cytotoxic activity against MCF-7 and HeLa cell lines. Moreover, in silico studies on most active compounds were also performed to understand the binding interaction of most active compounds with active sites of urease and α-glucosidase enzymes. Some compounds exhibited drug-like characteristics due to their lower cytotoxic and good ADME profiles.