Fragment-based virtual screening discovers potential new Plasmodium PI4KIIIβ ligands

Type III beta phosphatidylinositol 4-kinase (PI4KIIIβ) is the only clinically validated drug target in Plasmodium kinases and therefore a critical target in developing novel drugs for malaria. Current PI4KIIIβ inhibitors have solubility and off-target problems. Here we set out to identify new Plasmodium PI4K ligands that could serve as leads for the development of new antimalarial drugs by building a PPI4K homology model since there was no available three-dimensional structure of PfPI4K and virtually screened a small library of ~ 22 000 fragments against it. Sixteen compounds from the fragment-based virtual screening (FBVS) were selected based on ≤ − 9.0 kcal/mol binding free energy cut-off value. These were subjected to similarity and sub-structure searching after they had passed PAINS screening and the obtained derivatives showed improved binding affinity for PfPI4K (− 10.00 to − 13.80 kcal/mol). Moreover, binding hypothesis of the top-scoring compound (31) was confirmed in a 100 ns molecular dynamics simulation and its binding pose retrieved after the system had converged at about 10 ns into the evolution was described to lay foundation for a rationale chemical-modification to optimize binding to PfPI4K. Overall, compound 31 appears to be a viable starting point for the development of PPI4K inhibitors with antimalarial activity.Publikationsfonds ML

New sulphonamide pyrolidine carboxamide derivatives: Synthesis, molecular docking, antiplasmodial and antioxidant activities.

Carboxamides bearing sulphonamide functionality have been shown to exhibit significant lethal effect on Plasmodium falciparum, the causative agent of human malaria. Here we report the synthesis of thirty-two new drug-like sulphonamide pyrolidine carboxamide derivatives and their antiplasmodial and antioxidant capabilities. In addition, molecular docking was used to check their binding affinities for homology modelled P. falciparum N-myristoyltransferase, a confirmed drug target in the pathogen. Results revealed that sixteen new derivatives killed the parasite at single-digit micromolar concentration (IC50 = 2.40-8.30 μM) and compounds 10b, 10c, 10d, 10j and 10o scavenged DPPH radicals at IC50s (6.48, 8.49, 3.02, 6.44 and 4.32 μg/mL respectively) comparable with 1.06 μg/mL for ascorbic acid. Compound 10o emerged as the most active of the derivatives to bind to the PfNMT with theoretical inhibition constant (Ki = 0.09 μM) comparable to the reference ligand pyrazole-sulphonamide (Ki = 0.01 μM). This study identifies compound 10o, and this series in general, as potential antimalarial candidate with antioxidant activity which requires further attention to optimise activity

Experimental and In-Silico Investigation of Anti-Microbial Activity of 1-Chloro-2-Isocyanatoethane Derivatives of Thiomorpholine, Piperazine and Morpholine.

The Antibiogram properties of 1-chloro-2-isocyanatoethane derivatives of thiomorpholine (CTC), piperazine (CPC) and morpholine (CMC) were evaluated by the approved agar well diffusion, the minimum inhibitory concentration (MIC) and in silico techniques. A total of fourteen microbial cultures consisting of ten bacteria and four yeast strains were used in the biological study while affinity of the compounds for DNA gyrase, a validated antibacterial drug target, was investigated by docking method. Results indicate that both thiomorpholine and piperazine had zero activity against the Gram negative organisms tested. With morpholine, similar result was obtained except that cultures of Escherichia coli (ATCC 15442) and Salmonella typhi (ATCC 6539) presented with weak sensitivity (7-8 mm) as shown by the inhibition zone diameter (IZD) measurement. The Gram positive organisms were more sensitive to morpholine than the other compounds. The highest IZD values of 15-18 mm were achieved except for Streptococcus pneumoniae (ATCC 49619) in which mobility of the compound stopped after 12 mm. S. pneumoniae was resistant to both thiomorpholine and piperazine. The yeast strains were not sensitive to any of the studied compounds investigated. The MIC tests evaluated against a reference antibiotic show that while morpholine was most active at 4 μg.ml-1 against both B. cereus ATCC (14579) and B. subtilis, the least active compound was thiomorpholine which inhibited S. aureus (ATCC 25923) at 64 μg.ml-1. The three compounds demonstrated high affinity for the target protein (DNA gyrase) ranging from -4.63 to -5.64 Kcal/mol and even showed better ligand efficiencies than three known antibiotics; chlorobiocin, ciprofloxacin and tetracycline. This study identified the studied compounds as potential antibiotic leads with acceptable physicochemical properties and gave the molecular basis for the observed interactions between the compounds and the target protein which can be harnessed in structural optimization process

N-Myristoyl Transferase Inhibitors with Antifungal Activity in Quinolinequinone Series: Synthesis, In-silico Evaluation and Biological Assay

Communication in Physical Sciences 2020, 5(4): 431-436 Received 12 June 2020/Accepted 27 July 2020  A series of anilino and aryl derivatives of quinolinequinone and naphthoquinone were synthesized via Pd catalysed cross-couplings. The results of docking the compound series towards the binding site of fungal N-myristoyl transferase (NMT) indicated that the quinones favourably interacted with the protein at binding free energy ranges of -5.14 to -8.01 kcal/mol. In addition, Candida albican and Candida anthra were susceptible to many of synthesized molecules in vitro, at MIC range of 1.60 -25 μg/ml. However, some of the compounds which had binding interaction with NMT in docking calculations fails to demonstrated measurable antifungal effect; and that highlights the importance of target-ligand complex stability dynamic situations that characterize biological system. Analysis of predicted binding modes revealed interesting structure-activity-relationship that can provide information on activity optimization proces

Anti-Trypanosomal Activity of Nigerian Plants and Their Constituents

African trypanosomiasis is a vector-borne parasitic disease causing serious risks to the lives of about 60 million people and 48 million cattle globally. Nigerian medicinal plants are known to contain a large variety of chemical structures and some of the plant extracts have been screened for antitrypanosomal activity, in the search for potential new drugs against the illness. We surveyed the literatures on plants and plant-derived products with antitrypanosomal activity from Nigerian flora published from 1990 to 2014. About 90 plants were identified, with 54 compounds as potential active agents and presented by plant families in alphabetical order. This review indicates that the Nigerian flora may be suitable as a starting point in searching for new and more efficient trypanocidal molecules

Poses of the x-ray structure of cocrystallized ligand (in red) and the docked ligand (in green).

<p>Poses of the x-ray structure of cocrystallized ligand (in red) and the docked ligand (in green).</p

N'-(Pyridin-3-ylmethylene)benzenesulfonohydrazide: Crystal structure, DFT, Hirshfeld surface and in silico anticancer studies

A new Schiff base, N'-(pyridin-3-ylmethylene)benzenesulfonohydrazide, was synthesized and characterized by elemental analysis, IR, Mass, 1H NMR and 13C NMR spectroscopy, and single-crystal X-ray determination. The asymmetric molecule crystallized in the monoclinic crystal system and P2(1)/c space group. Crystal data for C12H11N3O2S: a = 9.7547(4) Å, b = 9.8108(4) Å, c = 13.1130(5) Å, β = 109.038(2)°, V = 1186.29(8) Å3, Z = 4, μ(MoKα) = 0.270 mm-1, Dcalc = 1.463 g/cm3, 13338 reflections measured (5.296° ≤ 2Θ ≤ 55.484°), 2790 unique (Rint = 0.0494, Rsigma = 0.0400) which were used in all calculations. The final R1 was 0.0345 (I > 2σ(I)) and wR2 was 0.0914 (all data). In the crystal structure of the compound C12H11N3O2S, molecules are linked in a continuous chain by intermolecular of N∙∙∙HN=N hydrogen bonds. The pyridine moiety is planar, while the benzenesulfonohydrazide group adopts a gauche conformation about C-S-N angle (105.54°). The Hirshfeld surface analysis and fingerprint plots were used to establish the presence, nature, and percentage contribution of the different intermolecular interactions, including N-H∙∙∙N, C-H∙∙∙O, C-H∙∙∙C, and π∙∙∙π interactions, with the C-H contacts having the most significant contribution. The pairwise interaction energies were calculated at the B3LYP/6-31G(d,p) level of theory, and interaction energy profiles showed that the electrostatic forces had the most significant contribution to the total interaction energies of the different molecular pairs in the crystal. In-silico technique was used to examine the compound as a possible anticancer agent. The molecule demonstrated zero violation of the criteria of Lipinski’s rule of five with a polar surface area of 116.03 Å2. The molecule displayed favorable binding interactions with ten selected validated anticancer protein targets ranging from -9.58 to -11.95 kcal/mol and -2.73 to -5.73 kcal/mol on scoring and rescoring, respectively, with London dG and Affinity dG scoring functions. Two proteins; farnesyl transferase and signaling protein, preferred interactions with the Schiff-base over their co-crystallized inhibitors according to London dG scoring. Analysis of binding poses indicated that the Schiff-base made contact with amino acid residues of the two proteins through the N-H, sulphonyl oxygen, and phenyl groups, and this could be exploited in chemical and structural modification towards activity optimization

Synthesis of hiomorpholine piperazine and and morpholine derivatives of 1-chloro-2-isocyanatoethane.

<p>Synthesis of hiomorpholine piperazine and and morpholine derivatives of 1-chloro-2-isocyanatoethane.</p