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ABSTRACT

Novel Zn(II)–benzohydrazide complexes have been synthesized using Zn(NO3)2·6H2O salt. All new synthesises were investigated by available analytical and spectral tools to demonstrate their formulae. Binuclear complexes were proposed with all ligands through pentadentate mode of bonding. Octahedral geometry was the only structural form proposed for complexes. Benzohydrazide derivatives coordinate by the same mode, which point to negligible effect of p-substituents on donor site environment. This mode was verified basically by IR and 1H, 13C NMR spectra. According to XRD patterns, crystallite particles of complexes were appeared in nanosized range. Such feature is preferable in variable application fields. Molecular modeling and molecular docking were interested in this study to strengthen experimental studies. One of these complexes [Zn(II)–H2L2] was examined to be an additive optimizing the performance of traditional fertilizer (NH4NO3) in planting corn hybrid. This complex significantly improved components of photosynthetic carbon assimilation as photosynthetic pigments, sucrose, and soluble sugars. Interestingly, the applied complex induced responses, which were consistently higher than those treated by traditional fertilizer (NH4NO3). Therefore, these results highlight the promising behavior of Zn(II)–H2L2complex in planting improvement.

Background: Human African trypanosomiasis is a fatal disease prevalent in approximately 36 sub-Saharan countries. Emerging reports of drug resistance in Trypanosoma brucei are a serious cause of concern as only limited drugs are available for the treatment of the disease. Pteridine reductase is an enzyme of Trypanosoma brucei. Methods: It plays a critical role in the pterin metabolic pathway that is absolutely essential for its survival in the human host. The success of finding a potent inhibitor in structure-based drug design lies within the ability of computational tools to efficiently and accurately dock a ligand into the binding cavity of the target protein. Here we report the computational characterization of Trypanosoma brucei pteridine reductase (Tb-PR) active-site using twenty-four high-resolution co-crystal structures with various drugs. Structurally, the Tb-PR active site can be grouped in two clusters; one with high Root Mean Square Deviation (RMSD) of atomic positions and another with low RMSD of atomic positions. These clusters provide fresh insight for rational drug design against Tb-PR. Henceforth, the effect of several factors on docking accuracy, including ligand and protein flexibility were analyzed using Fred. Results: The online server was used to analyze the side chain flexibility and four proteins were selected on the basis of results. The proteins were subjected to small-scale virtual screening using 85 compounds, and statistics were calculated using Bedroc and roc curves. The enrichment factor was also calculated for the proteins and scoring functions. The best scoring function was used to understand the ligand protein interactions with top common compounds of four proteins. In addition, we made a 3D structural comparison between the active site of Tb-PR and Leishmania major pteridine reductase (Lm- PR). We described key structural differences between Tb-PR and Lm-PR that can be exploited for rational drug design against these two human parasites. Conclusion: The results indicated that relying just on re-docking and cross-docking experiments for virtual screening of libraries isn’t enough and results might be misleading. Hence it has been suggested that small scale virtual screening should be performed prior to large scale screening.

Background: Cancer is one of the major health and social-economic problems despite considerable progress in its early diagnosis and treatment. Owing to the emergence and increase of multidrug resistance to various conventional drugs, and the continuing importance of health-care expenditure, many researchers have focused on developing novel and effective anticancer compounds. Objective: Chemical repositories provide a good platform to evaluate and exploit known chemical entities for the identification of other biological activities. In the present study, we have selected an in-house library of synthesized compounds based on two different pharmacophoric scaffolds to evaluate their cytotoxic potency on various cancer cell lines and mechanisms of action. Methods: A series of in-house synthesized quinazoline and quinazolino-benzothiadiazine derivatives were investigated for their anticancer efficacy against a panel of five cancer (DU145, MCF7, HepG2, SKOV3 and MDA-MB-231) and one normal (MRC5) cell lines. Furthermore, the active compound of the study was investigated to elucidate the mechanism of cytotoxicity by performing series of experiments such as cell cycle analysis, inhibition of tubulin polymerization, alteration of mitochondrial membrane potential, determination of endocytic pathway for drug uptake pathway and combination drug treatment. Results: Among all the tested compounds, fifteen of them exhibited promising growth-inhibitory effect (0.15- 5.0μM) and induced cell cycle arrest in the G2/M phase. In addition, the selected compounds inhibited the microtubule assembly; altered mitochondrial membrane potential and enhanced the levels of caspase-9 in MCF-7 cells. Furthermore, the active compound with a combination of drugs showed a synergistic effect at lower concentrations, and the drug uptake was mediated through clathrin-mediated endocytic pathway. Conclusion: Our results indicated that quinazoline and quinazolino-benzothiadiazine conjugates could serve as potential leads in the development of new anticancer agents.

The triazole ring system has emerged as an exciting prospect in the optimization studies of promising lead molecules in the quest for new drugs for clinical usage. Several marketed drugs possess these versatile moieties that are used in a wide range of medical indications. This stems from the unique intrinsic properties of triazoles, which impart stability to the basic pharmacophoric unit with an added advantage of being a bioisostere of different chemical functionalities. In the last decade, the use of triazoles as bioisosteres and linkers in the development of microtubule targeting agents has been extensively investigated. The present review highlights the advances in this promising area of drug discovery and development.

Background: Since deficit of acetylcholine has been evidenced in the Alzheimer’s disease (AD) patients, cholinesterase inhibitors are currently the most specified drug category for the remediation of AD. Method: In the present study, 16 compounds (1-16) with dicarbonyl skeletons have been synthesized and tested for their inhibitory potential in vitro against AChE and BChE using ELISA microtiter plate assays at 100 μg/mL. Since metal accumulation is related to AD, the compounds were also tested for their metal-chelation capacity. Results and Conclusion: All the investigated dicarbonyl compounds exerted none or lower than 30% inhibition against both cholinesterases, whereas compounds 2, 8 and 11 showed 37, 42, 41% of inhibition towards BChE, being the most active. The highest metal-chelation capacity was observed with compound 8 (53.58 ± 2.06%). POM and DFT analyses are in good harmonization with experimental data.

Background: Cholinesterase family consists of two sister enzymes; acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) which hydrolyze acetylcholine. Since deficit of acetylcholine has been evidenced in patients of Alzheimer's disease (AD), cholinesterase inhibitors are currently the most prescribed drugs for the treatment of AD. Objective: our aim in this article was to investigate the inhibitory potential of five known compounds (2-6) with spiro skeleton against AChE and BChE using ELISA microplate assays. In addition to their ChE inhibitory effect, their physico-chemical properties were also calculated. Moreover, the present work aims at investigating the charge/geometrical effect of a hypothetical pharmacophore or bidentate site in a bioactive group, on the inhibition efficiency of spiro compounds 2-6 by using Petra/Osiris/ molinspiration (POM) and X-ray analyses. Method: In the present study, five compounds (2-6) with spiro skeleton have been synthesized and tested in vitrofor their inhibitory potential against AChE and BChE using ELISA microtiter plate assays at 25 μg/mL. Results: Results revealed that three of the spiro compounds tested exert more than 50% inhibition against one of cholinesterases. Compound 5 displayed 68.73 ± 4.73% of inhibition toward AChE, whereas compound 6 showed 56.17 ± 0.83% of inhibition toward BChE; these two previously synthesized compounds have been the most active hits. Conclusions: Our data obtained from screening of compounds 2-6 against the two cholinesterases indicate that three of these show good potential to selectively inhibit AChE or BChE. Spiro compounds 2, 5, and 6 exhibited the most potent activity of the series against AChE or BChE with inhibition values in the range 55-70%.

The present study introduced the fabrication and electroanalytical characterization of a novel mirabegron (MIR) voltammetric screen-printed sensor. The sensing platform was based on zirconium oxide nanoparticles (ZrO2NPs) integrated printing carbon ink with enhanced electrocatalytic activity towards the electrooxidation of the MIR molecule at the electrode surface. Under the optimum measuring parameters, MIR exhibited an irreversible oxidation peak at 0.922 V with a diffusion-controlled reaction and the participation of one electron/proton in the electrooxidation process. The zirconium oxide nanoparticles based screen-printed electrodes (ZrO2NPs/SPEs) showed improved performance within the linear MIR concentration ranged from 10.0 to 261.8 ng ml−1and limit of detection (LOD) value of 2.72 ng ml−1. The introduced ZrO2NPs/SPEs offered higher sensitivity with the possibility of mass production and miniaturization compared with other MIR sensors. Based on the achieved selectivity, the presented electrodes can be applied for the simultaneous differential pulse voltammetric (DPV) monitoring of MIR in the presence of various degradation contaminates and excipients. Furthermore, the presented electroanalytical approach was tested for the sensitive quantification of MIR in biological samples and pharmaceutical formulations with acceptable recovery values in agreement with the official method.