Synthesis, UV-Vis Spectroscopic and Physico-chemical Characterization of Oxovanadyl Complexes of Lincomycin and Neomycin

In the recent past, the pharmaceutical modification of drug molecules by complexation with biologically relevant metals to improve their properties such as stability, dissolution rate, absorption and bioavailability has been extensively studied. In order to achieve better and enhanced medicinal activity, vanadyl complexes of the widely used lincomycin (Lin-van) and neomycin (Neo-van) have been synthesized and their physico-chemical properties examined. The UV-Vis absorption properties of these complexes were determined and their antimicrobial activities were tested against some pathogenic organisms viz: Proteus vulgaris, Klebsiella pneumonae, Escherichia coli and Staphylococcus aureus. In all cases, Neo-van showed better antimicrobial activity than Lin-van while both complexes showed better activity than the antibiotic lincomycin and the previously reported Cu-Lin. Keywords: lincomycin, neomycin, UV-Vis spectroscopy, Physico-chemical, Oxovanadyl, synthesis

Functional Stratification of Cancer Drugs through Integrated Network Similarity

Heterogeneity across tumors is the main obstacle in developing treatment strategies. Drug molecules not only perturb their immediate protein targets but also modulate multiple signaling pathways. In this study, we explored the networks modulated by several drug molecules across multiple cancer cell lines by integrating the drug targets with transcriptomic and phosphoproteomic data. As a result, we obtained 236 reconstructed networks covering five cell lines and 70 drugs. A rigorous topological and pathway analysis showed that chemically and functionally different drugs may modulate overlapping networks. Additionally, we revealed a set of tumor-specific hidden pathways with the help of drug network models that are not detectable from the initial data. The difference in the target selectivity of the drugs leads to disjoint networks despite sharing the exact mechanism of action, e.g., HDAC inhibitors. We also used the reconstructed network models to study potential drug combinations based on the topological separation, found literature evidence for a set of drug pairs. Overall, the network-level exploration of the drug perturbations may potentially help optimize treatment strategies and suggest new drug combinations.

Bio-Membrane Internalization Mechanisms of Arginine-Rich Cell-Penetrating Peptides in Various Species

Recently, membrane-active peptides or proteins that include antimicrobial peptides (AMPs), cytolytic proteins, and cell-penetrating peptides (CPPs) have attracted attention due to their potential applications in the biomedical field. Among them, CPPs have been regarded as a potent drug/molecules delivery system. Various cargoes, such as DNAs, RNAs, bioactive proteins/peptides, nanoparticles and drugs, can be carried by CPPs and delivered into cells in either covalent or noncovalent manners. Here, we focused on four arginine-rich CPPs and reviewed the mechanisms that these CPPs used for intracellular uptake across cellular plasma membranes. The varying transduction efficiencies of them alone or with cargoes were discussed, and the membrane permeability was also expounded for CPP/cargoes delivery in various species. Direct membrane translocation (penetration) and endocytosis are two principal mechanisms for arginine-rich CPPs mediated cargo delivery. Furthermore, the amino acid sequence is the primary key factor that determines the cellular internalization mechanism. Importantly, the non-cytotoxic nature and the wide applicability make CPPs a trending tool for cellular delivery.

GOx-assisted synthesis of pillar[5]arene based supramolecular polymeric nanoparticles for targeted/synergistic chemo-chemodynamic cancer therapy

Background Cancer is the most serious world's health problems on the global level and various strategies have been developed for cancer therapy. Pillar[5]arene-based supramolecular therapeutic nano-platform (SP/GOx NPs) was constructed successfully via orthogonal dynamic covalent bonds and intermolecular H-bonds with the assistance of glucose oxidase (GOx) and exhibited efficient targeted/synergistic chemo-chemodynamic cancer therapy. Methods The morphology of SP/GOx NPs was characterized by DLS, TEM, SEM and EDS mapping. The cancer therapy efficinecy was investigated both in vivo and in vitro. Results SP/GOx NPs can load drug molecules (Dox) and modify target molecule (FA-Py) on its surface conveniently. When the resultant FA-Py/SP/GOx/Dox NPs enters blood circulation, FA-Py will target it to cancer cells efficiently, where GOx can catalyst the overexpressed glucose to generate H2O2. Subsequently, the generated H2O2 in cancer cells catalyzed by ferrocene unit to form •OH, which can kill cancer cells. Furthermore, the loaded Dox molecules released under acid microenvironment, which can further achieve chemo-therapy. Conclusion All the experiments showed that the excellent antitumor performance of FA-Py/SP/GOx/Dox NPs, which provided an new method for pillar[5]arene-based supramolecular polymer for biomedical applications. Graphical Abstract

Molecular Docking and Molecular Dynamics Studies of Role of Anti-Allergic Medicines as Inhibitors Against Covid-19

The 2019-nCoV virus is a human-infectious coronavirus (CoV). Very few treatment options are available to healthcare professionals who are fighting this outbreak at the front. The main warning symptoms of COVID-19, the disease caused by the new coronavirus, are fever, fatigue, and a dry cough, sometimes it also causes cold-like symptoms like a runny nose which are sometimes similar to symptoms of allergies and sometimes difficult to differentiate between COVID-19 and allergies. The anti-allergic drug molecules can behave as good inhibitor against COVID-19. Molecular docking studies have been performed to examine the inhibitor properties of anti-allergic molecules against Covid-19. The searching of better inhibitors have been examined interns of various non-covalent interactions like hydrogen bond, halogen bond, vander waal’s interactions, alkyl-πand π-π interactions between small molecules (Anti-allergic medicines) with main protease of Covid-19 using molecular docking and Molecular Dynamics simulation which reveals that astemizole is best inhibitor among ten Anti-allergic drug molecules.

HobPre: accurate prediction of human oral bioavailability for small molecules

Human oral bioavailability (HOB) is a key factor in determining the fate of new drugs in clinical trials. HOB is conventionally measured using expensive and time-consuming experimental tests. The use of computational models to evaluate HOB before the synthesis of new drugs will be beneficial to the drug development process. In this study, a total of 1588 drug molecules with HOB data were collected from the literature for the development of a classifying model that uses the consensus predictions of five random forest models. The consensus model shows excellent prediction accuracies on two independent test sets with two cutoffs of 20% and 50% for classification of molecules. The analysis of the importance of the input variables allowed the identification of the main molecular descriptors that affect the HOB class value. The model is available as a web server at www.icdrug.com/ICDrug/ADMET for quick assessment of oral bioavailability for small molecules. The results from this study provide an accurate and easy-to-use tool for screening of drug candidates based on HOB, which may be used to reduce the risk of failure in late stage of drug development. Graphical Abstract

In silico ADME/Pharmacokinetic and Target Prediction Studies of Ethambutol as Drug Molecule

Background: The conventional approach for the development of any pharmaceutically active molecule is a time-consuming and costly process because the synthesis is followed by laboratory tests which are then followed by long clinical trials. Hence a faster approach is desired. This article discusses Ethambutol, a frontline anti-tubercular drug that has its properties predicted by the SwissADME tool and the results would be compared with the findings published in the literature. Objective: The main objective is to study the predicted and experimental ADME properties, compare them. As well as study the predicted targets and understand the use of SwissADME for designing other drug molecules. Method: SwissADME, an online tool for ADME prediction was used along with Swiss Target Prediction to understand the targets of the drug. Further, experimental data was obtained from the available scientific literature. Results: We found certain similarities between the predicted and experimental data. However, there were some variations, depending on the testing conditions. The results are interpreted ahead in the article. Conclusion: Ethambutol’s predicted ADME properties are discussed and as per findings from results, it can be concluded that other drug molecules can be similarly predicted using these tools. Also, based on predicted data we can reformulate and prepare some different preparations of the drug.

Cu-Catalyzed Allylation of Amines with Cyclopropyldiphenylsulfonium Trifluoromethanesulfonate

Cyclopropyldiphenylsulfonium salt is a famous ylide precursor that was previously extensively employed in the preparation of cyclic compounds and has been successfully utilized as an efficient allylation reagent in this work. The Cu-catalyzed reactions of cyclopropyldiphenylsulfonium trifluoromethanesulfonate with amines in the presence of an appropriate ligand provided the N-allylated products in good yields. Aliphatic/aromatic amines and primary/secondary amines were all mildly converted under the reaction conditions. This protocol was also applicable to N-functionalization of drug molecules, supplying the corresponding N-allylated compounds in satisfactory yields. The reaction showed good functional group tolerance, a wide range of substrates, and excellent chemoselectivity, which offered an interesting method for the synthesis of N-allyl amines.

Construction of N-heterocycles via Pd-mediated C–H activation/annulation strategies

N-heterocycles can be found in natural products and drug molecules, which are indispensable components in the area of organic synthesis, medicinal chemistry and material science. The construction of these N-containing...

Crystal Structure, Solubility, and Pharmacokinetic Study on a Hesperetin Cocrystal with Piperine as Coformer

Hesperetin (HES) is a key biological active ingredient in citrus peels, and is one of the natural flavonoids that attract the attention of researchers due to its numerous therapeutic bioactivities that have been identified in vitro. As a bioenhancer, piperine (PIP) can effectively improve the absorption of insoluble drugs in vivo. In the present study, a cocrystal of HES and PIP was successfully obtained through solution crystallization. The single-crystal structure was illustrated and comprehensive characterization of the cocrystal was conducted. The cocrystal was formed by two drug molecules at a molar ratio of 1:1, which contained O–H–O hydrogen bonds between the carbonyl and ether oxygen of PIP and the phenolic hydroxyl group of HES. In addition, a solubility experiment was performed on powder cocrystal in simulated gastrointestinal fluid, and the result revealed that the cocrystal improves the dissolution behavior of HES compared with that of the pure substance. Furthermore, HES’s bioavailability in the cocrystal was six times higher than that of pristine drugs. These results may provide an efficient oral formulation for HES.