Orally Bioavailable 4-Phenoxy-quinoline Compound as a Potent Aurora Kinase B Relocation Blocker for Cancer Treatment.

We investigated a novel 4-phenoxy-quinoline-based scaffold that mislocalizes the essential mitotic kinase, Aurora kinase B (AURKB). Here, we evaluated the impact of halogen substitutions (F, Cl, Br, and I) on this scaffold with respect to various drug parameters. Br-substituted LXY18 was found to be a potent and orally bioavailable disruptor of cell division, at sub-nanomolar concentrations. LXY18 prevents cytokinesis by blocking AURKB relocalization in mitosis and exhibits broad-spectrum antimitotic activity in vitro. With a favorable pharmacokinetic profile, it shows widespread tissue distribution including the blood-brain barrier penetrance and effective accumulation in tumor tissues. More importantly, it markedly suppresses tumor growth. The novel mode of action of LXY18 may eliminate some drawbacks of direct catalytic inhibition of Aurora kinases. Successful development of LXY18 as a clinical candidate for cancer treatment could enable a new, less toxic means of antimitotic attack that avoids drug resistance mechanisms.

Isolation and Identification of Bioactive Compounds with Antimicrobial Activity from Marine Facultative Anaerobe, Bacillus subtilis.

INTRODUCTION: The marine ecosystem contains many microbial species that produce unique, biologically active secondary metabolites with complex chemical structures. We aimed to isolate and identify bioactive compounds with antimicrobial properties produced by a facultative anaerobic strain of Bacillus subtilis (AU-RM-1), isolated from marine sediment. METHODOLOGY: We optimized the AU-RM-1 growth conditions, analyzed its growth kinetics and its phenotypic and genotypic characteristics. Extracts of the isolate were studied for antimicrobial activity against three clinically important microorganisms and the structure of the active compound was identified by spectroscopy. RESULTS: Antimicrobial activity of the AU-RM-1 DMSO extract was evaluated by disc diffusion assay and by serial dilution. The AU-RM-1 DMSO extract showed antimicrobial activity against Candida albicans, Escherichia coli, and Klebsiella pneumoniae. The bioactive fraction of the AURM- 1 DMSO extract was separated by TLC-bioautography at Rf = 0.49. We then used scanning electron microscopy (SEM) and transmission electron microscopy (TEM) to study the morphological changes in the bacterial cells treated with the isolated compound. It was observed that cells seemed to shrink, and the cell walls appeared to be damaged. A bioactive compound was identified, and its structure was examined by spectroscopic analysis: a LC-MS molecular ion peak (ESI) m/z (% of relative abundance) was calculated for C19H22O3: 298.38, and found to be C19H22O3 +1: 299.51 [M+1]. The chemical structure of the compound (2-(2-{8-methoxy-5aH,6H,7H,8H,9H, 9aH-naphtho[2,1-b]furan-7-yl}ethyl)furan) was determined using 1HNMR and 13CNMR, and its purity was confirmed by HPLC. Fifteen known and previously reported compounds were also identified, in addition to the novel compound; these were lipopeptides, antibiotics and chemical moieties. CONCLUSION: The facultative anaerobic marine organism Bacillus subtilis (AU-RM-1) produces a novel bioactive secondary metabolite with antimicrobial and antifungal activity.

Bioactive Efficacy of Novel Carboxylic Acid from Halophilic Pseudomonas aeruginosa against Methicillin-Resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) infections are increasingly causing morbidity and mortality; thus, drugs with multifunctional efficacy against MRSA are needed. We extracted a novel compound from the halophilic Pseudomonas aeruginosa using an ethyl acetate (HPAEtOAcE). followed by purification and structure elucidation through HPLC, LCMS, and 1H and 13C NMR, revealing the novel 5-(1H-indol-3-yl)-4-pentyl-1,3-oxazole-2-carboxylic acid (Compound 1). Molecular docking of the compound against the MRSA PS (pantothenate synthetase) protein was confirmed using the CDOCKER algorithm in BDS software with specific binding to the amino acids Arg (B:188) and Lys (B:150) through covalent hydrogen bonding. Molecular dynamic simulation of RMSD revealed that the compound-protein complex was stabilized. The proficient bioactivities against MRSA were attained by the HPAEtOAcE, including MIC and MBCs, which were 0.64 and 1.24 µg/mL, respectively; 100% biomass inhibition and 99.84% biofilm inhibition were observed with decayed effects by CLSM and SEM at 48 h. The hla, IrgA, and SpA MRSA genes were downregulated in RT-PCR. Non-hemolytic and antioxidant potential in the DPPH assay were observed at 10 mg/mL and IC50 29.75 ± 0.38 by the HPAEtOAcE. In vitro growth inhibition assays on MRSA were strongly supported by in silico molecular docking; Lipinski's rule on drug-likeness and ADMET toxicity prediction indicated the nontoxic nature of compound.

Marine biome-derived secondary metabolites, a class of promising antineoplastic agents: A systematic review on their classification, mechanism of action and future perspectives.

Cancer is one of the most deadly diseases on the planet. Over the past decades, numerous antineoplastic compounds have been discovered from natural resources such as medicinal plants and marine species as part of multiple drug discovery initiatives. Notably, several marine flora (e.g. Ascophyllum nodosum, Sargassum thunbergii) have been identified as a rich source for novel cytotoxic compounds of different chemical forms. Despite the availability of enormous chemically enhanced new resources, the anticancer potential of marine flora and fauna has received little attention. Interestingly, numerous marine-derived secondary metabolites (e.g., Cytarabine, Trabectedin) have exhibited anticancer effects in preclinical cancer models. Most of the anticancer drugs obtained from marine sources stimulated apoptotic signal transduction pathways in cancer cells, such as the intrinsic and extrinsic pathways. This review highlights the sources of different cytotoxic secondary metabolites obtained from marine bacteria, algae, fungi, invertebrates, and vertebrates. Furthermore, this review provides a comprehensive overview of the utilisation of numerous marine-derived cytotoxic compounds as anticancer drugs, as well as their modes of action (e.g., molecular target). Finally, it also discusses the future prospects of marine-derived drug developments and their constraints.

Computational Lock and Key and Dynamic Trajectory Analysis of Natural Biophors Against COVID-19 Spike Protein to Identify Effective Lead Molecules.

New pandemic infection of coronaviridae family virus spread to more than 210 countries with total infection of 1,136,851 and 62,955 (4.6%) deaths until 5th April 2020. Which stopped the regular cycle of humankind but the nature is consistently running. There is no micro molecule remedy found yet to restore the regular life of people. Hence, we decided to work on natural biophores against the COVID proteins. As a first step, major phytoconstituents of antiviral herbs like Leucas aspera, Morinda citrifolia, Azadirachta indica, Curcuma longa, Piper nigrum, Ocimum tenuiflorum, and Corallium rubrum collected and performed the lock and key analysis with major spike protein of COVID-19 to find the best fitting lead biophore using computational drug design platform. The results of protocol run showed, phytoconstituents of Morinda citrifolia and Leucas aspera were found lower binding energy range of - 55.18 to - 25.34 kcal/mol, respectively and compared with Hydroxychloroquine (HCQ) (- 24.29 kcal/mol) and Remdesivir (- 25.38 kcal/mol). The results conclude that, core skeletons chromen, anthracene 9, 11 dione and long-chain alkyl acids/ester-containing biophores showen high stable antagonistic affinity with S-protein. Which leads the breakdown of spike protein and ACE2 receptor complex formation and host mechanism of corono virus. In addition, the dynamic trajectory analysis confirmed the complete denaturation of spike protein by the molecule 4-(24-hydroxy-1-oxo-5-n-propyltetracosanyl)-phenol from Leucas aspera and stability of spike-ligand complex. These biophores will aid the researcher to fabricate new promising analogue and being recommended to assess its COVID-19 treatment.