Project description:A series of novel 2,5-disubstituted-1,3,4-oxadiazole derivatives were synthesized and screened for their antimicrobial and antioxidant activities. The assay indicated that compounds 3c, 3d, and 3i exhibited comparable antibacterial and antioxidant activity with first-line drugs. The structure activity relationship and molecular docking study of the synthesized compounds are also reported.
Project description:Nowadays, the discovery of a new non-toxic metal complex with biological activity represents a very active area of research. Two Cu+2 complexes, [Cu(L1)2(H2O)3] (C1) (HL1= N-(5-(4-methylphenyl)-[1,3,4]-thiadiazole-2-yl)-naphtalenesulfonamide) and [Cu(L2)2(py)2(H2O)] (C2) (HL2= N-(5-ethyl-[1,3,4]-thiadiazole-2-yl)-naphtalenesulfonamide), with two new ligands were synthesized. The X-ray crystal structures of the complexes were determined. In both complexes, Cu+2 is five-coordinated, forming a CuN2O3 and CuN4O chromophore, respectively. The ligands act as monodentate, coordinating the metal ion through a single Nthiadiazole atom; for the C2 complex, the molecules from the reaction medium (pyridine and water) are also involved in the coordination of Cu+2. The complexes have a distorted square pyramidal square-planar geometry. The compounds were characterized by FT-IR, electronic EPR spectroscopy, and magnetic methods. The nuclease activity studies confirm the complexes' capacity to cleave the DNA molecule. Using a xanthine-xanthine oxydase system, the SOD mimetic activity of the complexes was demonstrated. Cytotoxicity studies were carried out on two tumor cell lines (HeLa, WM35) and on a normal cell line (HFL1) using the MTT method, with cisplatin used as a positive control. The antibacterial activity of the complexes was investigated against two Gram-positive and two Gram-negative bacteria, and compared with Amoxicillin and Norfloxacin using the disk diffusion method. Both complexes showed in vitro biological activity but the C2 complex was more active. A lack of in vivo toxicity was demonstrated for the C2 complex by performing hepatic, renal, and hematological studies on Swiss mice.
Project description:The lipoteichoic acid (LTA) biosynthesis pathway has emerged as a promising antimicrobial therapeutic target. Previous studies identified the 1,3,4 oxadiazole compound 1771 as an LTA inhibitor with activity against Gram-positive pathogens. We have succeeded in making six 1771 derivatives and, through subsequent hit validation, identified the incorporation of a pentafluorosulfanyl substituent as central in enhancing activity. Our newly described derivative, compound 13, showed a 16- to 32-fold increase in activity compared to 1771 when tested against a cohort of multidrug-resistant Staphylococcus aureus strains while simultaneously exhibiting an improved toxicity profile against mammalian cells. Molecular techniques were employed in which the assumed target, lipoteichoic acid synthase (LtaS), was both deleted and overexpressed. Neither deletion nor overexpression of LtaS altered 1771 or compound 13 susceptibility; however, overexpression of LtaS increased the MIC of Congo red, a previously identified LtaS inhibitor. These data were further supported by comparing the docking poses of 1771 and derivatives in the LtaS active site, which indicated the possibility of an additional target(s). Finally, we show that both 1771 and compound 13 have activity that is independent of LtaS, extending to cover Gram-negative species if the outer membrane is first permeabilized, challenging the classification that these compounds are strict LtaS inhibitors.
Project description:The synthesis of several 1,2,5-oxadiazole-2-oxide (Furoxan) analogues is described herein. These compounds were prepared in an effort to probe the SAR around the phenyl substituent and oxadiazole core for our studies toward thioredoxin-glutathione reductase (TGR) inhibition and anti-schistosomal activity.
Project description:Dihydrofolate reductase (DHFR) inhibitors, as antibacterial agents, contain pyrimidine, pteridine, and azine moieties among many other scaffolds. Folic acid (FA), with a pteridine ring and amine group, was used as our focus scaffold, which was then conjugated with sulfonamides to develop new conjugates. The novel synthesized conjugates were characterized using infrared spectroscopy, and 1H and 13C nuclear magnetic resonance (NMR) spectral studies and consequently screened for antimicrobial activities against bacterial strains with ampicillin as a positive control. Compound DS2 has the highest zone of inhibition (36.6 mm) with a percentage activity index (%AI) value of 122.8% against S. aureus and a minimum inhibitory concentration (MIC) of 15.63 μg mL-1. DHFR enzyme inhibition was also evaluated using the synthesized conjugates through in vitro studies, and inhibition assays revealed that compound DS2 exhibited a 75.4 ± 0.12% (mean ± standard error of the mean (SEM)) inhibition, which is comparable with the standard DHFR inhibitor trimethoprim (74.6 ± 0.09%). The compounds attached to the unsubstituted aryl moiety of the sulfonamides revealed better inhibition against the bacterial strains as compared to the methyl substituted aryl sulfonamides. Molecular docking studies of the novel synthesized conjugates were also performed on the DHFR enzyme to identify the plausible binding modes to explore the binding mechanisms of these conjugates.
Project description:Background: Anti-tuberculosis drugs, mainly developed more than 60 years ago, combined with a poorly effective vaccine, have failed to eradicate tuberculosis. More worryingly, multi-resistant strains of Mycobacterium tuberculosis are constantly emerging. Innovative strategies are thus urgently needed to improve tuberculosis treatment. Recently, host-directed therapy (HDT) has emerged as a promising strategy to be used in adjunct with existing or future antibiotics, by improving innate immunity or limiting immunopathology. Here, we evaluated the impact of two host-directed compounds, namely MC3465 and MC3209, on the response of human monocytes-derived macrophages infected with Mycobacterium tuberculosis (MTB). Results: The expression of 181 genes was differentially regulated following MC3465 treatment (p-value < 0.05, log FC ≥ 0.5 and ≤ -0.5) after 4 h, with 53 being upregulated and 128 being downregulated. The expression of more genes was affected after 24h of treatment. 224 genes were upregulated and 652 genes downregulated. (p value < 0.05, log FC ≥ 0.5 and ≤ -0.5). We classified those differentially expressed genes by performing gene-set enrichment analysis using ClueGO cluster analysis. The gene set downregulated by MC3465 at 4 h was significantly enriched for genes associated with chemotaxis and cellular zinc ion homeostasis and cell chemotaxis. At 24 h, most of the downregulated genes belongs to the innate immune response and the cytokine response, with many genes belonging to the type I IFN pathway. Conclusions: Our results indicate that MC3465 alters zinc homeostasis in human macrophages.
Project description:Prion diseases currently have no effective therapy. These illnesses affect both animal and human populations, and are characterized by the conformational change of a normal self protein PrP(C) (C for cellular) to a pathological and infectious conformer, PrP(Sc) (Sc for scrapie). We used a well characterized tissue culture model of prion infection, where mouse neuroblastoma cells (N2a) were infected with 22L PrP(Sc), to screen compounds for anti-prion activity. In a prior study we designed a library of styryl based, potential imaging compounds which were selected for high affinity binding to Alzheimer's disease ?-amyloid plaques and good blood-brain barrier permeability. In the current study we screened this library for activity in the N2a/22L tissue culture system. We also tested the anti-prion activity of two clinically used drugs, trimipramine and fluphenazine, in the N2a/22L system. These were selected based on their structural similarity to quinacrine, which was previously reported to have anti-prion activity. All the compounds were also screened for toxicity in tissue culture and their ability to disaggregate amyloid fibrils composed of PrP and ?-amyloid synthetic peptides in vitro. Two of the imaging agents, 23I and 59, were found to be both effective at inhibiting prion infection in N2a/22L tissue culture and to be non-toxic. These two compounds, as well as trimipramine and fluphenazine were evaluated in vivo using wild-type CD-1 mice infected peripherally with 139A PrP(Sc). All four agents significantly prolonged the asymptomatic incubation period of prion infection (p<0.0001 log-rank test), as well as significantly reducing the degree of spongiform change, astrocytosis and PrP(Sc) levels in the brains of treated mice. These four compounds can be considered, with further development, as candidates for prion therapy.
Project description:Multi-drug resistance is a growing problem in the treatment of infectious diseases and the widespread use of broad-spectrum antibiotics has produced antibiotic resistance for many human bacterial pathogens. Advances in nanotechnology have opened new horizons in nanomedicine, allowing the synthesis of nanoparticles that can be assembled into complex architectures. Novel studies and technologies are devoted to understanding the mechanisms of disease for the design of new drugs, but unfortunately infectious diseases continue to be a major health burden worldwide. Since ancient times, silver was known for its anti-bacterial effects and for centuries it has been used for prevention and control of disparate infections. Currently nanotechnology and nanomaterials are fully integrated in common applications and objects that we use every day. In addition, the silver nanoparticles are attracting much interest because of their potent antibacterial activity. Many studies have also shown an important activity of silver nanoparticles against bacterial biofilms. This review aims to summarize the emerging efforts to address current challenges and solutions in the treatment of infectious diseases, particularly the use of nanosilver antimicrobials.
Project description:Discovery of novel anticandidal agents with clarified mechanisms of action, could be a rationalist approach against diverse pathogenic fungal strains due to the rise of resistance to existing drugs. In support to this hypothesis, in this paper, a series of benzimidazole-oxadiazole compounds were synthesized and subjected to antifungal activity evaluation. In vitro activity assays indicated that some of the compounds exhibited moderate to potent antifungal activities against tested Candida species when compared positive control amphotericin B and ketoconazole. The most active compounds 4h and 4p were evaluated in terms of inhibitory activity upon ergosterol biosynthesis by an LC-MS-MS method and it was determined that they inhibited ergosterol synthesis concentration dependently. Docking studies examining interactions between most active compounds and lanosterol 14-α-demethylase also supported the in vitro results.
Project description:The expansion of the novel coronavirus known as SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), COVID-19 (coronavirus disease 2019), or 2019-nCoV (2019 novel coronavirus) is a global concern over its pandemic potential. The need for therapeutic alternatives to stop this new pandemic is urgent. Nowadays, no efficacious therapy is available, and vaccines and drugs are underdeveloped to cure or prevent SARS-CoV-2 infections in many countries. Some vaccines candidates have been approved; however, a number of people are still skeptical of this coronavirus vaccines. Probably because of issues related to the quantity of the vaccine and a possible long-term side effects which are still being studied. The previous pandemics of infections caused by coronavirus, such as SARS-CoV in 2003, the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, HCoV-229E, and HCoV-OC43 were described in the 1960 s, -HCoV-NL63 isolated in 2004, and HCoV-HKU1identified in 2005 prompted researchers to characterize many compounds against these viruses. Most of them could be potentially active against the currently emerging novel coronavirus. Five membered nitrogen heterocycles with a triazole, imidazole, and thiazole moiety are often found in many bioactive molecules such as coronavirus inhibitors. This present work summarizes to review the biological and structural studies of these compound types as coronavirus inhibitors.