Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-associated mortalities worldwide. Therefore, it is crucial to develop a novel therapeutic option targeting localized and metastatic NSCLC. In this paper, we describe the synthesis and biological activity characterization of naphthoquinone derivatives bearing selective anticancer activity to NSCLC via a COX-2 mediated pathway. The biological evaluation of compounds 9–16 showed promising structure-dependent anticancer activity on A549 cells in 2D and 3D models. Compounds were able to significantly (p < 0.05) reduce the A549 viability after 24 h of treatment in comparison to treated control. Compounds 9 and 16 bearing phenylamino and 4-hydroxyphenylamino substituents demonstrated the most promising anticancer activity and were able to induce mitochondrial damage and ROS formation. Furthermore, most promising compounds showed significantly lower cytotoxicity to non-cancerous Vero cells. The in silico ADMET properties revealed promising drug-like properties of compounds 9 and 16. Both compounds demonstrated favorable predicted GI absorption values, while only 16 was predicted to be permeable through the blood–brain barrier. Molecular modeling studies identified that compound 16 is able to interact with COX-2 in arachidonic acid site. Further studies are needed to better understand the safety and in vivo efficacy of compounds 9 and 16.

Multiple antibiotic-resistant strains of Klebsiella pneumoniae can cause life-threatening infections. Bacterial enoyl-acyl carrier protein (ACP) reductases (ENRs) are considered critical targets for developing antibiotics. Our current study aims to identify inhibitors of K. pneumoniae ENRs (FabI and FabV). Due to the unavailability of experimental structures, protein models of FabI and FabV were predicted and validated in this study. Virtual screening of the 1930 FDA-approved drug database was conducted against the active site of the FabI protein with the help of the LEA3D server, and carfilzomib was chosen among the screened drugs for further docking studies. Carfilzomib, a proteasome inhibitor used in the treatment of multiple myeloma, was among the best-suited compounds obtained from the virtual screening and was found to be bactericidal in the in vitro experiment. Carfilzomib was docked against the active sites of the FabI and FabV proteins, and the ENR of Mycobacterium tuberculosis, InhA. Carfilzomib showed a high binding affinity with all three proteins. Molecular dynamics (MD) simulations were conducted following the docking studies. MD simulations revealed that carfilzomib binds strongly to the active sites of the above mentioned ENRs. Our study found that carfilzomib is a potential inhibitor of the ENRs of K. pneumoniae and M. tuberculosis. This is a possible mechanism of its bactericidal property against M. tuberculosis observed in vitro in addition to its predicted actions on zinc-dependent metalloprotease-1 and peptide deformylase, two other drug target enzymes of M. tuberculosis. Our study suggests that this drug could be used as a lead compound to develop antibiotics that can selectively act against ENRs of bacteria, without interfering with the activities of human proteasome. Communicated by Ramaswamy H. Sarma

Antimicrobial peptides (AMPs) are ancient innate immune components. Big defensins is a family of AMPs found in a restricted number of animal phyla, in particular mollusks where they have highly diversified. Big defensins are composed of a highly hydrophobic N-terminal region and a C-terminal β-defensin-like region, stabilized by three disulfide bridges. They have been shown to be active against both Gram-positive, Gram-negative bacteria and fungi. Antimicrobial aggregates called nanonets entrapping bacteria have been recently described as the mechanism of action of the Cg -BigDef1 from the oyster Crassostrea gigas . Specifically, the N-terminal domain of Cg -BigDef1 was identified as responsible of nanonet formation. In order to determine whether nanonets are specific to oyster Cg -BigDef1 or common to other big defensins outside this species, we assessed the potential entrapping of bacteria through nanonets of the big defensin from the scallop Argopecten purpuratus , namely Ap BD1. Recombinant Ap BD1 was produced as a fusion polypeptide which carried a N-terminal His6 tag, with a thrombin cleavage site before the mature peptide sequence and an unfolded C-terminal domain by mutating the last Cys to Arg. Activity of r Ap BD1 was assessed against the gram-positive bacteria Staphylococcus aureus SG511. r Ap BD1 inhibited bacterial growth. Moreover, strong immune staining of r Ap BD1 in numerous areas surrounding bacteria was observed. Overall, results suggest that r Ap BD1 entrap bacteria in peptide aggregates similar to those reported to Cg -BigDef1. This study demonstrates the conservation of nanonet formation across big defensins and supports further a role for the N-terminal domain in this conserved process.

Antibiotic resistance is a global concern. Two members of the bacterial genus Elizabethkingia, namely, E. anophelis and E. meningoseptica have raised much concern in recent years because of their resistance to multiple commonly used antibiotics. Identification of multidrug resistant and pan-drug resistant bacteria has propelled the search for new antibiotics that can act on unconventional targets. Researches are going on to find out the possibility of using bacterial ribonucleotide reductases as a novel target for antibiotic development. Through in silico evaluations, this study aims for characterization and functional annotation of ribonucleotide reductase enzymes of E. anophelis and E. meningoseptica. Binding affinities with these enzymes of the compounds that have shown promising results in inhibiting Pseudomonas aeruginosa growth by acting on its ribonucleotide reductase were also assessed by molecular docking and dynamics simulations. Insights from this study will help in battling these infections in the near future. Communicated by Ramaswamy H. Sarma