Candidiasis is an opportunistic fungal infection that is considered to be the most common in humans. Recently, Candida albicans infections have increased worldwide due to enlarged use of antifungals and medical devices, such as heart valves, vascular bypasses, dental implants, and catheters, where fungal biofilms can form. In this work, two cationic porphyrins were evaluated as photosensitizing agents for the photodynamic inactivation (PDI) of C. albicans under different culture conditions. The photosensitizers used were 5,10,15-tris[4-(3-N,N,N-trimethylamoniopropoxi)phenyl]-20-(4-trifluormethylphenyl) porphyrin (AB₃) and 5,10,15,20-tetrakis[4-(3-N,N,N-trimethylamoniopropoxy) phenyl]porphyrin (A₄). Both porphyrins were rapidly bound to cells in 5 min. Photodynamic treatment was performed using different concentrations of photosensitizer (0.5-5.0 µM) and different times of irradiation (5-30 min) with white light (90 mW/cm²). C. albicans planktonic cells treated with 2.5 and 5.0 µM were eliminated after 5 and 15 min of irradiation, respectively. The addition of reactive oxygen species scavengers showed that singlet molecular oxygen was involved in the photoinactivation. Also, a contribution of type I mechanism was detected in the yeast inactivation. These agents were also effective to photoinactivate C. albicans pseudohyphae suspended in PBS, producing a reduction of 6 log after 15 min of irradiation. Furthermore, the biofilms of C. albicans that incorporated the porphyrins (5 mM) during the proliferation stage were completely photoinactivated after 60 min of irradiation. Therefore, the results indicate both porphyrins present potential applications as a phototherapeutic agent for fungal inactivation under different culture conditions.

Free radicals play a significant role in various detrimental biological processes, including protein denaturation and lipid peroxidation, contributing to the development of numerous human diseases. Hence, investigating the antiradical potential of the synthesized compounds becomes crucial to determine whether they can mitigate the levels of free radicals and provide protection against oxidative stress in the human body. The aim of the present investigation is the synthesis, characterization, and study of antioxidant activity of the new ligand: N-[4-({2-[1-(pyridin-2-yl)ethylidene]hydrazinecarbothioyl}amino)phenyl]acetamide (HL) and Cu(II) coordination compounds with HL: [Cu(L)CH₃COO] (1), [{Cu(L)Cl}₂]·H₂O (2), [Cu(L)H₂O·DMF]NO₃ (3). The new thiosemicarbazone based on 4-aminoacetanilide was synthesized, and functionalized according to the organic synthesis procedure: synthesis of the isothiocyanate group and hydrazone following the nucleophilic addition reaction with the formation of the HL ligand. The HL was characterized by NMR, FTIR spectroscopy, and X-ray crystallography. Single crystal X-ray diffraction analysis elucidated the structures of thiosemicarbazone HL as well as complexes 1-3. The antiradical activity against the 2,2-azinobis-(3-ethylbenzothiazoline-6-sulphonate) radical cation (ABTS^•+) was evaluated for the compounds under examination: HL and copper(II) complexes 1–3. The obtained results are represented as semimaximal inhibitory concentrations (IC₅₀). The HL and complexes 1-3 possessed notable antioxidant activity with IC₅₀ values of 8.5±1.5, 47.44±1.9, 24.3±1.3, 23.3±0.9 µM, respectively. Thus, the ligand HL and complexes 2, 3 exhibit remarkable antioxidant activity, surpassing the activity of Trolox, a standard antioxidant utilized in medical applications. The tested ligand HL demonstrates an activity that is four times higher than that of Trolox. Among the copper(II) complexes, the antioxidant potency follows this sequence: Cu(L)H₂O·DMF]NO₃ ≥ [{Cu(L)Cl}₂]·H₂O ≥ [Cu(L)CH₃COO].

NAD⁺-dependent class-III histone deacetylases (HDACs), also known as sirtuins (SIRTs), comprise seven isoforms (SIRT1-7) that play key roles in maintaining cellular functions, regulating metabolic and homeostatic processes, and preventing oxidative stress damage. SIRT5 is located in the mitochondrial matrix (along with SIRT3, which shares some of its activities, and SIRT4). This isoform regulates the metabolism of ammonia, the tricarboxylic acid cycle (TCA), glycolysis, fatty acid oxidation, apoptosis, and the electron transport chain. Considering the potential of SIRT5 as a pharmacological target, several modulators, acting as both sirtuin-activating (STACs) and sirtuin-inhibiting compounds (STICs), have been published. SIRT5 deficiency is known to increase the severity of rheumatoid arthritis in rat model; so, its activation may exert an anti-inflammatory role. On this basis, we decided to focus our efforts on SIRT5 STACs, since only few selective SIRT5 activators have been reported in the literature so far.

In an attempt to identify novel anti-inflammatory agents, we considered the repositioning of several compounds belonging to our in-house library, also including some furan derivatives, active as antitubercular agents.

The compounds were screened by a SIRT5 promoter assay, and their SIRT5 desuccinylation activity was evaluated. Some of them showed interesting properties as SIRT5 activators and, most notably, no cytotoxic activity. The preliminary results of our ongoing studies will be presented.

Human serum transferrin (hTF) is an 80 kDa single-chain protein formed by two lobes (N and C), each containing a Fe³⁺ binding site. Depending on the number of Fe³⁺ bound, hTF exists in different forms. In addition to the apo- and holo-hTF, containing respectively no or two ferric ions, hTF can also occur in two monoferric forms. In these latter, only one Fe³⁺ is bound either to N- (Fe_N-hTF) or C-lobe (Fe_C-hTF).

As a consequence of the over expression of transferrin receptor on cancer cells, hTF has been proposed as a potential anticancer drug carrier. It has also been demonstrated that hTF can bind the anticancer agent cisplatin ([cis-Pt(NH₃)₂Cl₂]) and selectively deliver it to cancer cells. Although numerous studies have been conducted to determine the molecular mechanism of cisplatin binding to hTF, there are still divergent opinions on the cisplatin binding sites of hTF. This is mainly due to the substantial lack of direct structural information on the adducts formed by cisplatin and the different hTF forms.

In this context, we recently solved, for the first time, the crystallographic structures of the adducts formed upon reaction of the cisplatin with apo-hTF or Fe_C-hTF. The two structures show a different number of Pt-binding sites and could help to clarify the reactivity of the cisplatin towards the different forms of hTF.

An increase in secondary complications, hypercholesterolemia, diabetes mellitus, and blood pressure, are known to increase the risk of vascular diseases (VDs), causing more mortality and morbidity globally. VDs include the abnormal functioning of coronary, carotid, vertebral, cervical, visceral, abdominal, aortic, and peripheral vessels. Complications of microcirculation due to peripheral vascular insufficiency have received considerable attention owing to venous and arterial diseases. In such complicated situations, LTA4H, CASP3, ALOX5, PTGS1, and PTGS2 are considered significant protein targets. For example, LTA4H and ALOX5 are associated with atherosclerotic plaque formation, inflammation, and instability; CASP3 is involved in the apoptosis of vascular smooth muscle cells, while PTGS is involved in peripheral vascular resistance, platelet aggregation, vascular inflammation, and vasoconstriction. Thus, targeting expressions of these proteins could provide beneficial effects in combating the complications of vascular diseases. Thymoquinone (TQ) is one such active phytoconstituent found in the seeds of Nigella sativa, which possesses anti-inflammatory, antioxidant, antimicrobial, immunomodulatory, analgesic, anticancer, and antipyretic effects; however, it has not been explored for its activity in vascular complications. Accordingly, an in-silico investigation has been designed to evaluate the activity of TQ on the proteins mentioned above using molecular docking approaches. The findings suggested a strong molecular interaction between TQ and the targets. The docking profile depicted the binding affinity of LTA4H, CASP3, ALOX5, PTGS1, and PTGS2 with TQ having energies of -7.4 to -5.7 kcal/mol. Therefore, it can be concluded that TQ can be a potential phytoconstituent for vascular complications; however, more in-vitro and in-vivo studies are required.

The current study aims to create zaleplon-loaded self-emulsifying drug delivery systems (SEDDS) by varying the ratios of Phosal® 53 MCT, Tween 80, and Gelucire 44/14 as lipid, surfactant, and cosurfactant, respectively. The preparation of Phosal, Tween 80, and Gelucire 44/14 at 80%, 12%, and 8%, respectively, was found to be thermodynamically stable with a droplet size of 289 5 nm and charge of +13.9 1.5 mV. For the optimized formulation, dispersion properties such as particle size, viscosity, and pH of the SEDDS formulation were also measured. Diffusion studies revealed that the majority of the drug is encapsulated in the emulsion, resulting in the highest absorption capacity.

The improved in vitro dissolution behavior of zaleplon from SEDDS over control was observed, indicating its greater ability to retain zaleplon in a state of solubility. Ex vivo studies revealed a 3.65-fold increase in the level of permeation as SEDDS when compared to zaleplon alone in the pure state. SEDDS also increased bioavailability by 2.84-fold when tested in vivo against pure zaleplon suspension. The above SEDDS results show that SEDDS are capable of improving zaleplon oral bioavailability.

Natural oligoribonucleotides in complex with D-mannitol (ORN-D-M) exhibit a range of biological activities, including antiviral and antioxidant effects. In previous investigations, we observed that ORN-D-M demonstrated cytotoxicity on various malignant cell lines in a dose- and time-dependent manner. The aim of the current work was to determine the possible mechanisms of melanoma B16 cell inhibition by ORN-D-M. For this investigation, we examined the relative mRNA expression of various RNA sensors and their downstream-regulated pathways after ORN-D-M treatment of mouse melanoma B16 cells.

It was shown that ORN-D-M caused overexpression of ss-, dsRNA receptors Tlr3, 7, 8, and Eif2ak; the inflammation-suppressive subunit Nfkb1; and IFN type 1. Along with this, downregulation was observed in the mRNA expression of inflammatory cytokines Tnfa and Il1b, which are known as promoters of tumor progression. The ORN-D-M treatment affected apoptosis regulatory molecules, significantly decreasing the relative mRNA level of the antiapoptotic Bcl-2, and slightly increasing proapoptotic Bax.

Therefore, ORN-D-M can be an agonist to Tlr and Eif2ak receptors in melanoma cancer cells, causing the activation of proapoptotic signals through the Nfkb1-dependent pathway.

In order to fight malaria, a public health problem for which nearly half of the world’s population is at risk and responsible a life-threatening disease primarily found in tropical countries, for which the estimated number of deaths stood at 619 000 in 2021[1] and effective intersectoral coordination is recommended to facilitate concerted action [2], an original strategy is to design and synthesize new original drug candidates that are not recognized by the protein system involved in the drug efflux. Thus, taking into account our latest antimalarial derivatives described previously, namely new 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzenes [3], a series of novel structural analogues, the 1,3,5-tris[(4-(substituted-aminomethyl)phenoxy)methyl]benzene compounds 1, were designed, prepared, and evaluated for their in vitro antimalarial activity against the CQ-sensitive (3D7) and the CQ-resistant (W2) strains of the malaria parasite Plasmodium falciparum. The pharmacological data showed antimalarial activity with IC₅₀ values in the sub and μM range. In these new synthesized series, the 1,3,5-tris[(4-(substituted-aminomethyl)phenoxy)methyl]benzenes 1 bearing pyridinyl-alkylaminomethyl side chains at position 4 of the phenoxymethyl moieties displayed better activities than their homologs substituted with alkylaminoalkylaminomethyl side chains. Against the P. falciparum CQ-sensitive 3D7, the 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene 1p bearing pyridin-4-ylmethylaminomethyl side chains at position 4 of each of the phenoxymethyl groups was noticed to be the most active, with an IC₅₀ of 0.078 μM, while compound 1m substituted by pyridin-3-ylmethylaminomethyl side chains was found the most active ligands against the W2 strain with an IC₅₀ of 0. 073 µM. As the telomeres of P. falciparum have been previously reported as potential targets of these kinds of nitrogen heterocycles, some FRET melting assays have been carried out to test their ability to stabilize the parasitic telomeric G-quadruplexe.

[1] World malaria report 2022. Geneva: World Health Organization; 2022. Licence: CC BY-NC-SA 3.0 IGO.

[2] Ending the neglect to attain the Sustainable Development Goals: a road map for neglected tropical diseases 2021–2030. Geneva: World Health Organization; 2020. Licence: CC BY-NC-SA 3.0 IGO.

[3] Drugs Drug Candidates 2023, 2, 653-672; https://doi.org/10.3390/ddc2030033.

The four novel dinuclear complexes [{cis-PtCl(NH₃)₂(μ-4,4′-bipyridyl)ZnCl(terpy-Cl)}](ClO₄)₂, [{trans-PtCl(NH₃)₂(μ-4,4′-bipyridyl)ZnCl(terpy-Cl)}](ClO₄)₂, [{cis-PtCl(NH₃)₂(μ-pyrazine)ZnCl(terpy-Cl)}](ClO₄)₂ and [{trans-PtCl(NH₃)₂(μ-pyrazine)ZnCl(terpy-Cl)}](ClO₄)₂, derived from mononuclear [ZnCl(terpy-Cl)], (where terpy-Cl = 4’-chloro-2,2′:6′,2′′-terpyridine) were synthesized and characterized.

The possible DNA-protective effects of these complexes at different concentrations (25, 50, 100, 200, and 400 μg/ml) against hydroxyl and peroxyl radicals-induced DNA damage were determined using two in vitro antioxidant assays. Compared with the negative and positive controls, all complexes showed the significant DNA-protective effects at the concentrations tested, indicating scavenging activity on hydroxyl and peroxyl radicals generated by FeSO₄, H₂O₂, and AAPH.

In our previous study four dinuclear complexes of similar structure, analogues of these complexes but without chloride substituent in terpy ligand, were also used to evaluate the antigenotoxicity. Only [{cis-PtCl(NH₃)₂(μ-pyrazine)ZnCl(terpy)}](ClO₄)₂ had significant dose-dependent ability to inhibit peroxyl as well as hydroxyl radicals which is in line with the current study and antigenotoxicity of tested complex [{cis-PtCl(NH₃)₂(μ-pyrazine)ZnCl(terpy-Cl)}](ClO₄)₂. The significant DNA protective potential against hydroxyl and peroxyl radicals was also obtained for the remaining three tested dinuclear complexes. The presence of the chloride in the structure of newly synthesized complexes increase the electronic density on Zn center and, thus, decrease its nucleophilicity, which could be an explanation of their behavior. This data could be useful for further in vitro and in vivo biological evaluations of these antioxidative compounds.

Cytotoxicity of four newly synthesized dinuclear complexes [{cis-PtCl(NH₃)₂(μ-4,4′-bipyridyl)ZnCl(terpy-Cl)}](ClO₄)₂, [{trans-PtCl(NH₃)₂(μ-4,4′-bipyridyl)ZnCl(terpy-Cl)}](ClO₄)₂, [{cis-PtCl(NH₃)₂(μ-pyrazine)ZnCl(terpy-Cl)}](ClO₄)₂ and [{trans-PtCl(NH₃)₂(μ-pyrazine)ZnCl(terpy-Cl)}](ClO₄)₂, derived from mononuclear [ZnCl(terpy-Cl)], (where terpy-Cl = 4’-chloro-2,2′:6′,2′′-terpyridine) were evaluated on two colon carcinoma cell lines, HCT-116 and SW-480.

The effect of investigated complexes at different concentrations (0.1, 1, 10, 50, 100, 200 μg/ml) on colon carcinoma cell lines (HCT-116 and SW-480) was examined with MTT assay, and the IC₅₀ value was calculated, as a measure of cytotoxicity. Compared with the positive control (cisplatin), on SW-480 colon cancer cells, there is no significant citotoxicity of tested complexes and IC₅₀ values are higher than 200 µg/ml. If we compare IC₅₀ values between HCT-116 and SW-480 colon cancer cells, it is evident that HCT-116 cells are more sensitive on the treatment with these complexes. Tested complexes showed significant anticancer effect on HCT-116 colon carcinoma cell lines, but after 72 h of applied treatments. After 72 h, significant cytotoxic effect was evident only in HCT-116 cells after applied complexes [{cis-PtCl(NH₃)₂(μ-4,4′-bipyridyl)ZnCl(terpy-Cl)}](ClO₄)₂, [{trans-PtCl(NH₃)₂(μ-4,4′-bipyridyl)ZnCl(terpy-Cl)}](ClO₄)₂ and [{cis-PtCl(NH₃)₂(μ-pyrazine)ZnCl(terpy-Cl)}](ClO₄)₂. The best cytotoxic effect of all investigated complexes was pronounced after applying [{trans-PtCl(NH₃)₂(μ-4,4′-bipyridyl)ZnCl(terpy-Cl)}](ClO₄)₂ complex on HCT-116 colon cancer cells after 72 h (19.52±0.78 µg/ml).

In comparison with previously studied four analogues of these complexes but without chlorinated terpy ligand, cytotoxic effect of all complexes is lower. Obviously, the presence of the chloride in the structure of [ZnCl(terpy-Cl)] subunit of newly synthesized complexes influenced their behavior due to exchanged electronic communication between metal centers.