Current development of 5-nitrofuran-2-yl derivatives as antitubercular agents.

Pulmonary tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (MTB) and still remains one of the foremost fatal infectious diseases, infecting nearly a third of the worldwide population. The emergencies of multidrug-resistant and extensively drug-resistant tuberculosis (MDR and XDR-TB) prompt the efforts to deliver potent and novel anti-TB drugs. Research aimed at the development of new anti-TB drugs based on nitrofuran scaffold led to the identification of several candidates that were effective against actively growing as well as latent mycobacteria with unique modes of action. This review focuses on the recent advances in nitrofurans that could provide intriguing potential leads in the area of anti-TB drug discovery.

Discovery of novel natural products as dual MNK/PIM inhibitors for acute myeloid leukemia treatment: Pharmacophore modeling, molecular docking, and molecular dynamics studies.

MNK-2 and PIM-2 kinases play an indispensable role in cell proliferation signaling pathways linked to tyrosine kinase inhibitors resistance. In this study, pharmacophore modeling studies have been conducted on the co-crystalized ligands of MNK-2 and PIM-2 enzyme crystal structures to determine the essential features required for the identification of potential dual inhibitors. The obtained pharmacophore features were then screened against a library of 270,540 natural products from the ZINC database. The matched natural molecules were docked into the binding sites of MNK-2 and PIM-2 enzymes. The compounds with high docking scores with the two enzymes were further subjected to MM-GBSA calculations and ADME prediction. This led to the identification of compound 1 (ZINC000085569211), compound 2 (ZINC000085569178), and compound 3 (ZINC000085569190), with better docking scores compared to the reference co-crystallized ligands of MNK-2 and PIM-2. Moreover, compounds 1‒3 displayed better MM-GBSA binding free energies compared to the reference ligands. Finally, molecular dynamics (MD) study was used to assess the interaction stability of the compounds with MNK-2. To this end, compounds 1 and 3 bound strongly to the target during the whole period of MD simulation. The findings of the current study may further help the researchers in the discovery of novel molecules against MNK-2 and PIM-2.

Bioinspired imidazo[1,2-a:4,5-c']dipyridines with dual antiproliferative and anti-migrative properties in human cancer cells: The SAR investigation.

Herein, we report the design, synthesis and evaluation of novel bioinspired imidazo[1,2-a:4,5c']dipyridines. The structural optimization identified four anti-proliferative compounds. Compounds 11, 18, 19 and 20 exhibited excellent anticancer activities in vitro with IC50 of 0.4-5 µM against three human cancer cell lines (MDA-MB-468, MDA-MB-435s and MDA-MB-231). These four compounds induced apoptosis in MDA-MB-231 cells in a dose-dependent manner, targeting different apoptotic proteins expression: 11 increased the expression of pro-apoptotic Bax protein while 18-20 reduced the level of anti-apoptotic Bcl-2 protein. Compounds 18 and 19 also reduced MDA-MB-231 cells proliferation as measured by Ki-67 staining. Furthermore, compounds were also tested for the ability to inhibit cell migration in the highly aggressive human MDA-MB-435s cell line. Six compounds of this series (8, 15, 18, 22, 23, 24) inhibited cell migration by 41-50% while four compounds (20, 25, 27, 30) inhibited the migration by 53-62% in wound-healing experiments. Interestingly, compound 20 presented both antiproliferative and anti-migration activities and might be a promising anti-metastatic agent for cancer treatment.

Potential Deoxycytidine Kinase Inhibitory Activity of Amaryllidaceae Alkaloids: An In Silico Approach.

BACKGROUND: Plants of the Amaryllidaceae family have been under intense scrutiny for the presence of a couple of alkaloidal secondary metabolites with endued cytotoxic activity, such as pancratistatin (1), 7-deoxypancratistatin (2), narciclasine (3), 7-deoxynarciclasine (4), trans-dihydronarciclasine (5), and 7-deoxy-trans-dihydronarciclasine (6). Nevertheless, preclinical evaluation of these alkaloids has been put on hold because of the limited quantity of materials available from isolation. AIM: To explore the underlying cytotoxic molecular mechanisms of the Amaryllidaceae alkaloids (1-6) and to assess their absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles using chemoinformatic tools. MATERIALS AND METHODS: AutoDock 4.0 software along with different in silico chemoinformatic tools, namely PharmMapper, Molinspiration, MetaPrint2D, and admetSAR servers, were used to assess the drugability of the Amaryllidaceae alkaloids (1-6). RESULTS: Deoxycytidine kinase (dCK) (PDB: 1P60) was predicted as a potential target with fitting score of 5.574. In silico molecular docking of (1-6) into dCK revealed good interactions, where interesting hydrogen bonds were observed with the amino acid residues-Gly-28 and Ser-35-located in the highly conserved P-loop motif. This motif plays a special role in dCK function. Contrary to (1), in silico pharmacokinetic results have shown good absorption and permeation and thus good oral bioavailability for (2-6). CONCLUSION: The in silico docking data have proposed that the reported cytotoxic activity of the Amaryllidaceae alkaloids (1-6) could be mediated through dCK inhibition. In addition, the ADMET profile of these alkaloids is promising and thus (1-6) could be candidates for future drug development.

Development of stability-indicating methods for cefquinome sulphate.

The degradation behavior of cefquinome sulphate in alkaline medium at different temperatures was investigated using both first derivative spectrophotometric and HPLC methods. The drug degradation was found to be pH and temperature dependant. The pH-rate profile indicated a first order dependence of Kobs on [OH(-)] at pHs ranging between 9 and 11. Arrhenius plot obtained at pH 10 was linear between 65° and 100°C. The estimated activation energy of the hydrolysis was found to be 21.1 kcal mol(-1). Stability-indicating thin-layer chromatographic method for the separation of the drug and its alkaline hydrolysis product has been developed.

Total synthesis of (+)-trans-dihydronarciclasine utilizing asymmetric conjugate addition.

A highly efficient short-step construction of the common phenanthridine skeleton of pancratistatin-class alkaloids was accomplished in enantiomerically pure form using chiral ligand-controlled asymmetric conjugate addition. The utility of the intermediate was demonstrated by the total synthesis of (+)-trans-dihydronarciclasine with mild oxidation from an amine to an amide as a key step.