Oxiconazole Potentiates Gentamicin against Gentamicin-Resistant Staphylococcus aureus In Vitro and In Vivo.

Amid the mounting burden of multidrug-resistant (MDR) bacterial infections on health care worldwide, drug repurposing, a time and cost-effective strategy to identify new applications for drugs approved for other indications, can effectively fill the void in the current antibiotic pipeline. In this study, we have repurposed a topical antifungal agent, oxiconazole, in combination with gentamicin against skin infections caused by multidrug-resistant Staphylococcus aureus. Oxiconazole was identified as having antibacterial activity against S. aureus via whole-cell screening assays against clinically relevant bacterial pathogens. It exhibited a potent in vitro profile, including equipotent activity against clinical drug-susceptible and -resistant S. aureus and Enterococcus spp. Checkerboard assays and time-kill kinetics studies demonstrated its concentration-dependent killing and ability to synergize with the approved antibiotics daptomycin and gentamicin against susceptible and MDR S. aureus strains. Oxiconazole also significantly eradicated preformed S. aureus biofilms in vitro. Eventually, in an assessment of its ability to generate resistant S. aureus mutants via serial passaging, oxiconazole displayed an extremely low propensity for developing stable resistance in S. aureus. Its in vivo efficacy alone and in combination with synergistic antibiotics was assessed in a murine superficial skin infection model of S. aureus, where it strongly synergized with gentamicin, exhibiting superior activity to the untreated control and drug-alone treatment groups. Thus, oxiconazole can be repurposed as an antibacterial alone and in combination with gentamicin against susceptible and gentamicin-resistant S. aureus infections. IMPORTANCE Staphylococcus aureus, which causes the majority of nosocomial and community-acquired infections globally, is a WHO high-priority pathogen for antibiotic research and development. In addition to invasive infections, it is the causative agent of moderate to severe skin infections, with an increasing prevalence of infections caused by MDR strains such as methicillin-resistant S. aureus (MRSA). Our study highlights the repurposing of oxiconazole, a topical antifungal agent, as an ideal candidate for combination therapy with gentamicin against susceptible and drug-resistant S. aureus skin infections due to its extremely low propensity for resistance generation in S. aureus, activity against MDR strains, bactericidal killing kinetics alone and in combination, broad antifungal efficacy, and excellent safety and tolerability profile.

Automated Radiosynthesis and Molecular Docking Studies of Coumarin- Triazole Hybrid with fluorine-18: A feasibility study.

BACKGROUND: Fluorine-18 is one of the promising radiotracers that can report target specific information related to its physiology to understand the disease status through the PET modality. In the current study, the radiochemical synthesis, purification, and molecular docking studies of fluorine-18 (18F) radiolabeled coumarin-triazole hybrid have been performed. OBJECTIVE: To develop target specific fluorine-18 radiotracer for the diagnosis in oncology. METHODS: GE Tracer-lab FX2N module with few modifications in the line connections was used for the radiosynthesis and purification of target molecule [18F]SG-2, 4-((2,6-dimethylmorpholino) methyl)-7-((1-(4-(fluoro-18F) benzyl)-1H-1,2,3-triazol-4-yl) oxy)-2H-chromen-2-one, through the nucleophilic radiofluorination mechanism. The radiochemical purity was measured by HPLC, and TLC analytical methods. The kryptofix levels were also evaluated by using the TLC method. The residual solvents like DMF, ethanol were measured using GC. The Schrödinger drug discovery suite 2018 was used to study the protein and ligand interactions. RESULTS: The quality control parameters revealed the purity, chemical identity, and limits of residual solvents. The radiochemical purity was 95.5 ± 2.3%, and dimethylformamide solvent limit was 89 ± 3 ppm. The molecular docking results had suggested that the cold target molecule has made strong electronic interactions and showed the possible pharmacokinetic (ADME) properties with galectin-1 protein. Overall, these results showed that [[18F]SG-2 radiolabeling with 18F radionuclide was feasible, and support of molecular docking studies suggest possible interactions with Galectin- 1. CONCLUSION: we reported a feasibility study for labeling coumarin-triazole hybrid with fluorine-18 through aromatic nucleophilic fluorination reaction (SNAr).

Human Galectin-1 and Its Inhibitors: Privileged Target for Cancer and HIV.

Galectin 1(Gal-1), a ß-galactoside binding mammalian lectin of 14KDa, is implicated in many signalling pathways, immune responses associated with cancer progression and immune disorders. Inhibition of human Gal-1 has been regarded as one of the potential therapeutic approaches for the treatment of cancer, as it plays a major role in tumour development and metastasis by modulating various biological functions viz. apoptosis, angiogenesis, migration, cell immune escape. Gal-1 is considered as a biomarker in diagnosis, prognosis and treatment condition. The overexpression of Gal-1 is well established and seen in many types of cancer progression like osteosarcoma, breast, lung, prostate, melanoma, etc. Gal-1 greatly accelerates the binding kinetics of HIV-1 to susceptible cells, leading to faster viral entry and a more robust viral replication by specific binding of CD4 cells. Hence, the Gal-1 is considered a promising molecular target for the development of new therapeutic drugs for cancer and HIV. The present review laid emphasis on structural insights and functional role of Gal-1 in the disease, current Gal-1 inhibitors and future prospects in the design of specific Gal-1 inhibitors.

Synthesis and Biological Evaluation of Novel Heterocyclic Imines Linked Coumarin- Thiazole Hybrids as Anticancer Agents.

BACKGROUND: Human Galectin-1, a protein of lectin family showing affinity towards ß-galactosides has emerged as a critical regulator of tumor progression and metastasis, by modulating diverse biological events including homotypic cell aggregation, migration, apoptosis, angiogenesis and immune escape. Therefore, galectin-1 inhibitors might represent novel therapeutic agents for cancer. METHODS: A new series of heterocyclic imines linked coumarin-thiazole hybrids (6a-6r) was synthesized and evaluated for its cytotoxic potential against a panel of six human cancer cell lines namely, lung (A549), prostate (DU-145), breast (MCF-7 & MDA-MB-231), colon (HCT-15 & HT-29) using MTT assay. Characteristic apoptotic assays like DAPI staining, cell cycle, annexin V and Mitochondrial membrane potential studies were performed for the most active compound. Furthermore, Gal-1 inhibition was confirmed by ELISA and fluorescence spectroscopy. RESULTS: Among all, compound 6g {3-(2-(2-(pyridin-2-ylmethylene) hydrazineyl) thiazol-4-yl)-2H-chromen-2- one} exhibited promising growth inhibition against HCT-15 colorectal cancer cells with an IC50 value of 1.28 ± 0.14 µM. The characteristic apoptotic morphological features like chromatin condensation, membrane blebbing and apoptotic body formation were clearly observed with compound 6g on HCT-15 cells using DAPI staining studies. Further, annexin V-FITC/PI assay confirmed effective early apoptosis induction by treatment with compound 6g. Loss of mitochondrial membrane potential and enhanced ROS generation were confirmed with JC-1 and DCFDA staining method, respectively by treatment with compound 6g, suggesting a possible mechanism for inducing apoptosis. Moreover, flow cytometric analysis revealed that compound 6g blocked G0/G1 phase of the cell cycle in a dose-dependent manner. Compound 6g effectively reduced the levels of Gal-1 protein in a dose-dependent manner. The binding constant (Ka) of 6g with Gal-1 was calculated from the intercept value which was observed as 1.9 x 107 M-1 by Fluorescence spectroscopy. Molecular docking studies showed strong interactions of compound 6g with Gal-1 protein. CONCLUSION: Our studies demonstrate the anticancer potential and Gal-1 inhibition of heterocyclic imines linked coumarin-thiazole hybrids.