Harnessing the power of gold: advancements in anticancer gold complexes and their functionalized nanoparticles.

Cancer poses a formidable challenge, necessitating improved treatment strategies. Metal-based drugs and nanotechnology offer new hope in this battle. Versatile gold complexes and functionalized gold nanoparticles exhibit unique properties like biologically inert behaviour, outstanding light absorption, and heat-conversion abilities. These nanoparticles can be finely tuned for drug delivery, enabling precise and targeted cancer therapy. Their exceptional drug-loading capacity and low toxicity, stemming from excellent stability, biocompatibility, and customizable shapes, make them a promising option for enhancing cancer treatment outcomes and improving diagnostic imaging. Leveraging these attributes, researchers can design more effective and targeted cancer therapeutics. The potential of functionalized gold nanoparticles to advance cancer treatment and diagnostics holds a promising avenue for further exploration and development in the fight against cancer. This review article delves into the finely tuned attributes of functionalized gold nanoparticles, unveiling their potential for application in drug delivery for precise and targeted cancer therapy.

Cellular apoptosis and cell cycle arrest as potential therapeutic targets for eugenol derivatives in Candida auris.

Candida auris, the youngest Candida species, is known to cause candidiasis and candidemia in humans and has been related to several hospital outbreaks. Moreover, Candida auris infections are largely resistant to the antifungal drugs currently in clinical use, necessitating the development of novel medications and approaches to treat such infections. Following up on our previous studies that demonstrated eugenol tosylate congeners (ETCs) to have antifungal activity, several ETCs (C1-C6) were synthesized to find a lead molecule with the requisite antifungal activity against C. auris. Preliminary tests, including broth microdilution and the MUSE cell viability assay, identified C5 as the most active derivative, with a MIC value of 0.98 g/mL against all strains tested. Cell count and viability assays further validated the fungicidal activity of C5. Apoptotic indicators, such as phosphatidylserine externalization, DNA fragmentation, mitochondrial depolarization, decreased cytochrome c and oxidase activity and cell death confirmed that C5 caused apoptosis in C. auris isolates. The low cytotoxicity of C5 further confirmed the safety of using this derivative in future studies. To support the conclusions drawn in this investigation, additional in vivo experiments demonstrating the antifungal activity of this lead compound in animal models will be needed.

Modulation of key antioxidant enzymes and cell cycle arrest as a possible antifungal mode of action of cinnamaldehyde based azole derivative.

Although Candida auris was only identified in the year 2009, it has rapidly spread in more than a dozen countries and is proving more deadly and notorious. In our previous studies, we reported on the tremendous antifungal potential of a series of cinnamaldehyde based azole derivatives against fluconazole susceptible and resistant clinical isolates of Candida albicans and identified a promising lead molecule (6f). In this study, the effect of this compound on the viability and physiology of cell death in C. auris was assessed. The impact of compound 6f on cell cycle, oxidative stress enzymes and transcriptional profile of genes encoding these oxidative stress enzymes was also analysed. The results confirmed that compound 6f possessed the minimum inhibitory concentration of 0.98 µg/mL and prevented the growth and caused death in yeast cells. Furthermore, the compound at subinhibitory and inhibitory concentrations blocked the cell cycle in C. auris at S phase and G2/M phase and inhibited expression as well as activity of antioxidant enzymes that resulted in production of reactive oxygen species. Altogether, compound 6f showed potential antifungal activity against a virulent strain of C. auris and was able to induce oxidative stress and arrested cell cycle in C. auris and therefore, it can be considered as a strong candidate for antifungal drug development against C. auris.

Quorum Sensing and Biofilm Disrupting Potential of Imidazole Derivatives in Chromobacterium violaceum Using Antimicrobial and Drug Discovery Approaches.

Population of drug-resistant bacteria have increased at an alarming rate in the past few decades. The major reason for increasing drug resistance is the lack of new antibiotics and limited drug targets. It has therefore been a vital task to develop new antibiotics with different drug targets. Two such targets are biofilm formation and quorum sensing. Quorum sensing is cell to cell communication used by bacteria that initiates many important survival processes and aids in establishing pathogenesis. Both biofilm and quorum sensing are inter-related processes and play a major role in physiological and pathogenesis processes. In this study, five novel imidazole derivatives (IMA-1-IMA-5) were synthesised and tested for their antibacterial and anti-quorum sensing activities against Chromobacterium violaceum using different in silico and in vitro techniques following the standard protocols. In silico results revealed that all compounds were able to effectively bind to and interact sufficiently with the target protein CviR. CviR is a protein to which autoinducers bind to initiate the quorum sensing process. In silico results also revealed that the compounds generated favourable structural dynamics implying that the compounds would be able to effectively bind to CviR and inhibit quorum sensing. Susceptibility results revealed that IMA-1 is the most active of all the derivatives against both planktonic cells and biofilms. Qualitative and quantitative evaluation of anti-quorum sensing activity at sub-inhibitory concentrations of these compounds also revealed high activity for IMA-1. Down-regulation of most of the quorum sensing genes when cells were treated with the test compounds affirmed the high anti-quorum sensing activities of these compounds. The results from this study are promising and urges on the use of anti-quorum sensing and biofilm disrupting molecules to combat multi-drug resistance problem.

Citral derivative activates cell cycle arrest and apoptosis signaling pathways in Candida albicans by generating oxidative stress.

For combating life-threatening infections caused by Candida albicans there is an urgent requirement of new antifungal agents with a targeted activity and low host cytotoxicity. Manipulating the mechanistic basis of cell death decision in yeast may provide an alternative approach for future antifungal therapeutics. Herein, the effect of an active citral derivative (Cd1) over the physiology of cell death in C. albicans was assessed. The viability of C. albicans SC5314 cells was determined by broth microdilution assay. The crucial morphological changes and apoptotic markers in Cd1-exposed yeast cells were analyzed. Subsequently the results confirmed that Cd1 arrested growth and caused death in yeast cells. Furthermore, this molecule inhibited antioxidant enzymes that resulted in production of reactive oxygen species. DNA fragmentation and condensation, phosphatidylserine exposure at the outer leaflet of cell membrane, mitochondrial disintegration as well as accumulation of cells at G2/M phase of the cell cycle were recorded. Altogether, this derivative induced apoptotic-type cell death in C. albicans SC5314.

Piperidine based 1,2,3-triazolylacetamide derivatives induce cell cycle arrest and apoptotic cell death in Candida auris.

Introduction: The fungal pathogen Candida auris, is a serious threat to public health and is associated with bloodstream infections causing high mortality particularly in patients with serious medical problems. As this pathogen is generally resistant to all the available classes of antifungals, there is a constant demand for novel antifungal drugs with new mechanisms of antifungal action. Objective: Therefore, in this study we synthesised six novel piperidine based 1,2,3-triazolylacetamide derivatives (pta1-pta6) and tested their antifungal activity and mechanism of action against clinical C. auris isolates. Methods: Antifungal susceptibility testing was done to estimate MIC values of piperidine derivatives following CLSI recommended guidelines. MUSE Cell Analyzer was used to check cell viability and cell cycle arrest in C. auris after exposure to piperidine derivatives using different kits. Additionally, fluorescence microscopy was done to check the effect of test compound on C. auris membrane integrity and related apoptotic assays were performed to confirm cellular apoptosis using different apoptosis markers. Results: Out of the six derivatives; pta1, pta2 and pta3 showed highest active with MIC values from 0.24 to 0.97 µg/mL and MFC ranging from 0.97 to 3.9 µg/mL. Fungicidal behaviour of these compounds was confirmed by cell count and viability assay. Exposure to test compounds at sub-inhibitory and inhibitory concentrations resulted in disruption of C. auris plasma membrane. Further in-depth studies showed that these derivatives were able to induce apoptosis and cell cycle arrest in S-phase. Furthermore, the compounds demonstrated lower toxicity profile. Conclusion: Present study suggests that the novel derivatives (pta1-pta3) induce apoptotic cell death and cell cycle arrest in C. auris and could be potential candidates against C. auris infections.

Citral and its derivatives inhibit quorum sensing and biofilm formation in Chromobacterium violaceum.

With an upsurge in multidrug resistant bacteria backed by biofilm defence armours, there is a desperate need of new antibiotics with a non-traditional mechanism of action. Targeting bacteria by misguiding them or halting their communication is a new approach that could offer a new way to combat the multidrug resistance problem. Quorum sensing is considered to be the achilles heel of bacteria that has a lot to offer. Since, both quorum sensing and biofilm formation have been related to drug resistance and pathogenicity, in this study we synthesised new derivatives of citral with antiquorum sensing and biofilm disrupting properties. We previously reported antimicrobial and antiquorum sensing activity of citral and herein we report the synthesis and evaluation of citral and its derivatives (CD1-CD3) for antibacterial, antibiofilm and antiquorum sensing potential against Chromobacterium violaceum using standard methods. Preliminary results revealed that CD1 is the most active of all the derivatives. Qualitative and quantitative evaluation of antiquorum sensing activity at sub-inhibitory concentrations of these compounds also revealed high activity for CD1 followed by CD2, CD3 and citral. These compounds also inhibit biofilm formation at subinhibitory concentrations without causing any bacterial growth inhibition. These results were replicated by RT-qPCR with down regulation of the quorum sensing genes when C. violaceum was treated with these test compounds. Overall, the results are quite encouraging, revealing that biofilm and quorum sensing are interrelated processes and also indicating the potential of these derivatives to impede bacterial communication and biofilm formation.

Unravelling the anticancer potential of a square planar copper complex: toward non-platinum chemotherapy.

Coordination compounds from simple transition metals are robust substitutes for platinum-based complexes due to their remarkable anticancer properties. In a quest to find new metal complexes that could substitute or augment the platinum based chemotherapy we synthesized three transition metal complexes C1-C3 with Cu(ii), Ni(ii), and Co(ii) as the central metal ions, respectively, and evaluated them for their anticancer activity against the human keratinocyte (HaCaT) cell line and human cervical cancer (HeLa) cell lines. These complexes showed different activity profiles with the square planar copper complex C1 being the most active with IC50 values lower than those of the widely used anticancer drug cisplatin. Assessment of the morphological changes by DAPI staining and ROS generation by DCFH-DA assay exposed that the cell death occurred by caspase-3 mediated apoptosis. C1 displayed interesting interactions with Ct-DNA, evidenced by absorption spectroscopy and validated by docking studies. Together, our results suggest that binding of the ligand to the DNA-binding domain of the p53 tumor suppressor (p53DBD) protein and the induction of the apoptotic hallmark protein, caspase-3, upon treatment with the metal complex could be positively attributed to a higher level of ROS and the subsequent DNA damage (oxidation), generated by the complex C1, that could well explain the interesting anticancer activity observed for this complex.

Azole Based Acetohydrazide Derivatives of Cinnamaldehyde Target and Kill Candida albicans by Causing Cellular Apoptosis.

Opportunistic fungal pathogens including Candida albicans are responsible for the alarming rise in hospital acquired infections and millions of deaths worldwide. The current treatment modalities are not enough to handle this situation, and therefore, new treatment modalities and strategies are desperately needed. In this direction, we synthesized a series of azole based acetohydrazide derivatives of cinnamaldehyde and subjected it to antifungal activity evaluation. Preliminary antifungal activity evaluation revealed tremendous antifungal potential of some of the derivatives against fluconazole susceptible and resistant clinical isolates of Candida albicans. Although all the compounds in the series are structurally similar except for the presence of different substituents on the phenyl ring of the acetohydrazide pendent, they sharply differed in their activity profile. Further mechanism of action studies revealed that these compounds have an apoptotic effect on C. albicans confirmed via Annexin V-FITC staining and TUNEL assay.

Probing the antibacterial and anticancer potential of tryptamine based mixed ligand Schiff base Ruthenium(III) complexes.

Development of new chemotherapeutic agents to treat microbial infections and recurrent cancers is of pivotal importance. Metal based drugs particularly ruthenium complexes have the uniqueness and desired properties that make them suitable candidates for the search of potential chemotherapeutic agents. In this study, two mixed ligand Ru(III) complexes [Ru(Cl)2(SB)(Phen] (RC-1) and [Ru(Cl)2(SB)(Bipy)] (RC-2) were synthesised and characterized by elemental analysis, IR, UV-Vis, 1H, 13C NMR spectroscopic techniques and their molecular structure was confirmed by X-ray crystallography. Antibacterial activity evaluation against two Gram-positive (S. pneumonia and E. faecalis) and four Gram-negative strains (P. aurogenosa, K. pneumoniae, S. enterica, and E. coli) revealed their moderate antibacterial activity with MIC value of ≥250 µg/mL. Anticancer activity evaluation against a non-small lung cancer cell line (H1299) revealed the tremendous anticancer activity of these complexes which was further validated by DNA binding and docking results. DNA binding profile of the complexes studied by UV-Visible and fluorescence spectroscopy showed an intercalative binding mode with CT-DNA and an intrinsic binding constant in the range of 3.481-1.015× 105 M-1. Both the complexes were also found to exert weak toxicity to human erythrocytes by haemolytic assay compared to cisplatin. Potential of these complexes as anticancer agents will be further delineated by in vivo studies.

Synergistic antifungal effect of cyclized chalcone derivatives and fluconazole against Candida albicans.

The occurrence of invasive fungal diseases, particularly in immunocompromised patients, is life-threatening and increases the economic burden. The rising problem of multi-drug resistance is becoming a major concern for clinicians. In addition, a repertoire of antifungal agents is far less in number than antibacterial drugs. To combat these problems, combination therapy has gained a lot of interest. We previously reported the synergistic interaction of some mono- and bis-dihydropyrimidinone and thione derivatives with fluconazole and amphotericin B for combination antifungal therapy. In this study we used the same approach and synthesized different azole and non-azole derivatives of mono-(M) and bis-(B) chalcones and evaluated their antifungal activity profile alone and in combination with the most commonly used antifungal drug - fluconazole (FLC) - against seven FLC susceptible and three FLC resistant clinically isolated Candida albicans strains. Based on the minimum inhibitory concentration results, the bis-derivatives showed lower MIC values compared to their mono-analogues. Both fractional inhibitory concentration index and isobologram results revealed mostly synergistic, additive or indifferent interactions between the tested compounds and FLC against different Candida isolates. None of the tested compounds showed any effect on energy dependent R6G efflux, revealing that they do not reverse the mechanism of drug efflux. However, surprisingly, these compounds profoundly decreased ergosterol biosynthesis and showed down regulation of ERG11 gene expression, which is the possible mechanism of reversal of azole drug resistance by these compounds. These results provide a platform for further research to develop pyrimidinone/thione ring containing compounds as promising new antifungal agents, which could be used in antifungal combination therapy.

Cyclization of hydrazones of 2-acetyl-1-naphthol and 1-acetyl-2-naphthol with triphosgene. Synthesis of Spiro naphthoxazine dimers.

Cyclization of hydrazones derived from 2-acetyl-1-naphthol and 1-acetyl-2-naphthol with triphosgene gave naphtho[1,2-e]-1,3-oxazines, naphtho[2,1-e]-1,3-oxazines or their spiro dimers depending on the molar ratio of triphosgene used for the cyclization.