Selectivity Index Research Articles

Diverse bioactive secondary metabolites from Aspergillus terreus: antimicrobial, anticancer, and anti-SARS-CoV-2 activity studies.

Owing to its high interest as prolific source of diverse bioactive compounds referred in our previous research work, we have scaled-up the fermentation of themarine Aspergillus terreus LGO13 on a liquid culture medium to isolate and identify the very minor/further promising bioactive secondary metabolites and to study their antibacterial, cytotoxic, and antiviral properties. Twenty-three known bioactive metabolites, including the recently discovered microbial natural product N-benzoyl-tryptophan (1), were obtained herein. Their structures were determined using HR-ESI-MS 1D/2D NMR spectroscopy and data from the literature. The biological properties of the microbial extract and the resulting compounds were examined using a set of microorganisms, cervix carcinoma KB-3-1, nonsmall cell lung cancer (NSCLC) A549, and coronavirus (SARS-CoV-2), respectively. Molecular docking (MD) simulations were used to investigate the potential targets of the separated metabolites as anti-SARS-CoV-2 drugs. According to the current study, a viral protein that may be the target of anticovid drugs is a papain-like protease (PLpro), and chaetominine (2) appears to be a viable choice against this protein. We evaluated the antiviral efficacy of chaetominine (2), fumitremorgin C (6), and azaspirofuran A (9) against SARS-CoV-2 based on MD data. Chaetominine (2) and azaspirofuran A (9) displayed intermediate selectivity indices (SI=6.6 and 3.2, respectively), while fumitremorgin C (6) displayed a high selectivity index (SI=19.77). These findings show that fumitremorgin C has promising antiviral action against SARS-CoV-2.

Design, synthesis and molecular modeling of pyrazoline based coumarin derivatives as tubulin polymerization inhibitors

A series of coumarin-pyrazoline hybrids was synthesized by cyclization of the coumarin chalcones with hydrazine hydrate and phenyl hydrazine through 1,4-addition on α,β-unsaturated carbonyl system. The synthesized derivatives were evaluated for their cytotoxicity against HCT116, MCF7 and BJ-1 cell lines. Among them, compounds 5d and 5f showed the best selectivity indices (IC50= 13.2 and 12.3 µM (HCT116), 5.0 and 5.5 µM (MCF7) and 26.2 and 26.5 µM (BJ-1), respectively). Derivative 5d revealed an inhibitory effect on tubulin assembly (IC50= 6.53 µM), and CDK2 activity (IC50= 0.47 µM). Induction of apoptosis was observed in MCF-7 cells after treatment with derivative 5d which was associated with a significant decrease in Bcl-2 level and 3-fold increase in Bax level. Moreover, derivative 5d revealed an anti-migration activity as detected by wound healing assay. The active compound 5d was docked within the β tubulin active site to investigate the protein-ligand interactions illustrating a unique binding mode with better score than colchicine (-8.5 kcal/mol). Those studies, along with pharmacokinetics predictions, provided a base for further optimization of compound 5d as a potential anti-tubulin agent.

Synthesis of Substituted 1,2,4-Triazole-3-Thione Nucleosides Using E. coli Purine Nucleoside Phosphorylase.

1,2,4-Triazole derivatives have a wide range of biological activities. The most well-known drug that contains 1,2,4-triazole as part of its structure is the nucleoside analogue ribavirin, an antiviral drug. Finding new nucleosides based on 1,2,4-triazole is a topical task. The aim of this study was to synthesize ribosides and deoxyribosides of 1,2,4-triazole-3-thione derivatives and test their antiviral activity against herpes simplex viruses. Three compounds from a series of synthesized mono- and disubstituted 1,2,4-triazole-3-thione derivatives were found to be substrates for E. coli purine nucleoside phosphorylase. Of six prepared nucleosides, the riboside and deoxyriboside of 3-phenacylthio-1,2,4-triazole were obtained at good yields. The yields of the disubstituted 1,2,4-triazol-3-thiones were low due to the effect of bulky substituents at the C3 and C5 positions on the selectivity of enzymatic glycosylation for one particular nitrogen atom in the triazole ring. The results of cytotoxic and antiviral studies on acyclovir-sensitive wild-type strain HSV-1/L2(TK+) and acyclovir-resistant strain (HSV-1/L2/RACV) in Vero E6 cell culture showed that the incorporation of a thiobutyl substituent into the C5 position of 3-phenyl-1,2,4-triazole results in a significant increase in the cytotoxicity of the base and antiviral activity. The highest antiviral activity was observed in the 3-phenacylthio-1-(β-D-ribofuranosyl)-1,2,4-triazole and 5-butylthio-1-(2-deoxy-β-D-ribofuranosyl)-3-phenyl-1,2,4-triazole nucleosides, with their selectivity indexes being significantly higher than that of ribavirin. It was also found that with the increasing lipophilicity of the nucleosides, the activity and toxicity of the tested compounds increased.

Comprehensive Analysis of Curcumin Zinc Oxide Nanoparticles, Synthesis, Characterization, and Cytogenotoxic Profiling.

Curcumin from turmeric (Curcuma longa) has traditionally been used due to its pharmacological properties, such as anticancer, anti-inflammatory, cholesterol-lowering, and antioxidant activities, but has had limitations in use due to low bioavailability. Nanoparticles have protuberant efficacies to diagnose or cure a variety of diseases, including tumors, by fine-tuning their size, structure, and physicochemical characteristics. This study aims to develop a new dosage form of curcumin nanoparticles with zinc oxide to enhance its therapeutic efficacy against cancer and cause no damage to genetics. Curcumin zinc oxide nanoparticles were prepared and characterized by using a Zeta sizer, ultraviolet (UV)-spectrophotometer, scanning electron microscope (SEM), and Fourier transform infrared (FTIR) spectroscopy. Different concentrations range from 40 to 0.078 μg/mL, and these nanoparticles were evaluated for their anticancer activity by colorimetric analysis (MTT assay) on normal (Vero) and cancerous cell lines (MCF-7) and genotoxicity by the comet assay. The spherical-shaped curcumin zinc oxide nanoparticles of 189 nm size were prepared with characteristic functional groups. The selectivity index of curcumin zinc oxide nanoparticles, calculated from IC50 values, is 4.60 > 2.0, showing anticancer potential comparable to tamoxifen. The genetic damage index of the highest concentration (40 μg/mL) of curcumin zinc oxide nanoparticles was 0.08, with a percent fragmentation of 8%. The results suggest that nanoparticles of curcumin zinc oxide produced better anticancer effects and did not cause any significant damage to the DNA. Consequently, further research is required to ensure the development of a safe and quality dosage form of nanoparticles for proper utilization.

Separation of quinoline from quinoline/2-methylnaphthalene using deep eutectic solvents: Experimental and COSMO-RS prediction

The high-temperature coal tar wash oil contains two valuable components, namely, quinoline and 2-methylnaphthalene. These two components are challenging to separate during the deep processing. To address this issue, the COSMO-RS (Conductor-like Screening Mode for Real Solvent) model was utilized to identify them as a potential deep eutectic solvents (DESs) extractant. Based on the calculated infinite dilution activity coefficient, the performance indexes of DESs, including selectivity, solubility, and performance index were determined and utilized to identify high-performance extractants for the quinoline/2-methylnaphthalene system. Finally five DESs were selected based on these indexes, they are DES1 formed by Choline chloride: propionic acid with the molar ratio of 1:1, similarly, DES2 is Choline chloride:oxalic acid of 1:1, DES3 Tetraethylammonium chloride:propionic acid of 1:1, DES4 Tetraethylammonium bromide:itaconic acid of 1:2 and DES5 Tetraethylammonium bromide:propionic acid of 1:2. The liquid–liquid phase equilibrium experiments of the aforementioned five DESs at different temperatures (30 ℃, 40 ℃, and 50 ℃) under atmospheric pressure were conducted. The results showed that five kinds of DESs had good extraction effect on quinoline. The DESs formed by choline chloride and anhydrous oxalic acid had the best extraction effect. The quantum chemical single-molecule optimization of different HBDs and HBAs in DESs, intermolecular interaction energy analysis and independent gradient modeling shows that it is mainly induced by the formation of shared electron pairs by providing empty orbitals from DESs and lone pair of electrons from the quinoline molecule, and the main force is the weak hydrogen bonding force.

N-Hydroxypiridinedione: A Privileged Heterocycle for Targeting the HBV RNase H.

Hepatitis B virus (HBV) remains a global health threat. Ribonuclease H (RNase H), part of the virus polymerase protein, cleaves the pgRNA template during viral genome replication. Inhibition of RNase H activity prevents (+) DNA strand synthesis and results in the accumulation of non-functional genomes, terminating the viral replication cycle. RNase H, though promising, remains an under-explored drug target against HBV. We previously reported the identification of a series of N-hydroxypyridinedione (HPD) imines that effectively inhibit the HBV RNase H. In our effort to further explore the HPD scaffold, we designed, synthesized, and evaluated 18 novel HPD oximes, as well as 4 structurally related minoxidil derivatives and 2 barbituric acid counterparts. The new analogs were docked on the RNase H active site and all proved able to coordinate the two Mg2+ ions in the catalytic site. All of the new HPDs effectively inhibited the viral replication in cell assays exhibiting EC50 values in the low μM range (1.1-7.7 μM) with low cytotoxicity, resulting in selectivity indexes (SI) of up to 92, one of the highest reported to date among HBV RNase H inhibitors. Our findings expand the structure-activity relationships on the HPD scaffold, facilitating the development of even more potent anti-HBV agents.

Phthalazine Sulfonamide Derivatives as Carbonic Anhydrase Inhibitors. Synthesis, Biological and in silico Evaluation.

Carbonic Anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide involved in several biological processes. They show a wide diversity in tissue distribution and their subcellular localization. Twenty-two novel phthalazine derivatives were designed, synthesized, and evaluated against four human isoforms: hCA I, hCA II, hCA IX, and hCA XII. Compounds appeared to be very active mostly against hCA IX (7) and hCA I (6) isoforms being more potent than reference drug acetazolamide (AAZ). Some compounds appeared to be very selective with a selectivity index up to 13.8. Furthermore, docking was performed for some of these compounds on all isoforms to understand the possible interactions with the active site. Additionally, the most active compounds against hCA IX were subjected to cell viability assay. The anticancer activity of the compounds (3 a-d, 5 d, 5 i, and 5 m) was investigated using two human breast cancer cell lines, i. e. MCF-7 and MDA-MB-231 cells, and the normal counterpart, namely MCF10-A cells.

Synthesis, characterization, biomolecule-binding and preliminary anticancer properties of PtCl(N^N^O) with naphthalenyl-containing tridentate ligand

A tridentate Schiff base ligand was synthesized via the reaction of 2-hydroxynpthaldehyd with N-phenyl-o-phenylenediamine. The obtained ligand was utilized in synthesizing Pt-L2 [PtCl(N^N^O)]. The ligand and Pt-L2 were characterized by IR, NMR and mass spectroscopies as well as elemental analysis. The DNA-binding of Pt-L2 was examined by fluorescence quenching using the EB-DNA adduct method. The apparent affinity for the compound toward ct-DNA was nearly twice the affinity of ethidium bromide. Changes in the relative viscosity induced by platinum complexes of ct-DNA indicated an intercalation mode of binding for Pt-L2 and covalent binding for the second platinum compound, Pt-L1, synthesized from 3-ethoxysalicyaldehyde and N-phenyl-o-phenylenediamine. BSA-binding by Pt-L2 indicated the spontaneous formation of an adduct with the protein with good binding affinity (7.7 × 104). The anticancer activities of Pt-L2 were evaluated against two cancer cell lines and compared to that of Pt-L1 and cisplatin. Pt-L2 has better IC50 values, possibly because of its highly π-delocalized planar system. Moreover, selectivity index for Pt-L2 is high (SI = 168) which is one of the criteria for potential chemotherapeutic agents (higher than that observed for cisplatin (SI = 37)).

(5S)-5-Benzylswainsonines as potent and selective inhibitors of Golgi α-mannosidase II: synthesis, enzyme evaluation and molecular modelling

Development of novel anti-cancer therapeutics based on Golgi α-mannosidase II (GMII) inhibition is considerably impeded by an undesired co-inhibition of lysosomal α-mannosidase leading to severe side-effects. In this contribution, we describe a fully stereoselective synthesis of (5S)-5-[4-(halo)benzyl]swainsonines as highly potent and selective inhibitors of GMII. The synthesis starts from a previously reported aldehyde readily available from l-ribose, and the key features include an intramolecular reductive amination with substrate-controlled stereoselectivity and a late-stage derivatisation of the benzyl group via ipso-substitution. These novel swainsonine analogues were found to be nanomolar inhibitors of the Golgi-type α-mannosidase AMAN-2 (Ki = 23–75 nM) with excellent selectivity (selectivity index = 205–870) over the lysosomal-type Jack bean α-mannosidase. Finally, molecular docking and pKa calculations were performed to provide more insight into the structure of the inhibitor:enzyme complexes, and a pair interaction energy analysis (FMO-PIEDA) was carried out to rationalise the observed potency and selectivity of the inhibitors.

Design, synthesis and anti-inflammatory assessment of certain substituted 1,2,4-triazoles bearing tetrahydroisoquinoline scaffold as COX 1/2-inhibitors

Aiming to discover effective and safe non-steroidal anti-inflammatory agents, a new set of 1,2,4-triazole tetrahydroisoquinoline hybrids 9a-g, 11a-g and 12a-g was synthesized and evaluated as inhibitors of COX-1 and COX-2. In order to overcome the adverse effects of highly selective COX-2 and non-selective COX-2 inhibitors, the compounds of this study were designed with the goal of obtaining moderately selective COX-2 inhibitors. In this study compounds 9e, 9g and 11f are the most effective derivatives against COX-2 with IC50 values 0.87, 1.27 and 0.58 µM, respectively which are better than or comparable to the standard drug celecoxib (IC50 = 0.82 µM) but with lower selectivity indices as required by our goal design. The results of the in vivo anti-inflammatory inhibition test revealed that compounds 9e, 9g and 11f displayed a higher significant anti-inflammatory activity than celecoxib at all-time intervals. In addition, these compounds significantly decreased the production of inflammatory mediators PGE-2, TNF-ɑ and IL-6. Compounds 9e, 9g and 11f had a safe gastric profile compared to indomethacin, also compound 11f (ulcerogenic index = 1.33) was less ulcerous than the safe celecoxib (ulcerogenic index = 3). Moreover, histopathological investigations revealed a normal architecture of both paw skin and gastric mucosa after oral treatment of rats with compound 11f. Furthermore, molecular docking studies were performed on COX-1 and COX-2 to study the binding pattern of compounds 9e, 9g and 11f on both isoenzymes.

Discovery of Di(het)arylmethane and Dibenzoxanthene Derivatives as Potential Anticancer Agents.

A family of bifunctional dihetarylmethanes and dibenzoxanthenes is assembled via a reaction of acetals containing a 2-chloroacetamide moiety with phenols and related oxygen-containing heterocycles. These compounds demonstrated selective antitumor activity associated with the induction of cell apoptosis and inhibition of the process of glycolysis. In particular, bis(heteroaryl)methane containing two 4-hydroxy-6-methyl-2H-pyran-2-one moieties combine excellent in vitro antitumor efficacy with an IC50 of 1.7 µM in HuTu-80 human duodenal adenocarcinoma models with a high selectivity index of 73. Overall, this work highlights the therapeutic potential of dimeric compounds assembled from functionalized acetals and builds a starting point for the development of a new family of anticancer agents.

Designing Chromane Derivatives as α2A-Adrenoceptor Selective Agonists via Conformation Constraint.

Enhancing the selectivity of alpha2-adrenoceptor (α2A-AR) agonists remains an unresolved issue. Herein, we reported the design of an α2A-AR agonist using the conformation constraint method, beginning with medetomidine. The structure-activity relationship indicated that the 8-substituent of chromane derivatives exerted the most pronounced effect on α2A-AR agonistic activity. Compounds A9 and B9 were identified as the most promising, exhibiting EC50 values of 0.78 and 0.23 nM, respectively. Their selectivity indexes surpassed dexmedetomidine (DMED) by 10-80 fold. In vivo studies demonstrated that both A9 and B9 dose-dependently increased the loss of righting reflex in mice, with ED50 values of 1.54 and 0.138 mg/kg, respectively. Binding mode calculations and mutation studies suggested the indispensability of the hydrogen bond between ASP1283.32 and α2A-AR agonist. In particular, A9 and B9 showed no dual reverse pharmacological effect, a characteristic exhibited by DMED in α2A-AR activation.

Quantitative Analysis of Isopimpinellin from Ammi majus L. Fruits and Evaluation of Its Biological Effect on Selected Human Tumor Cells.

Ammi majus L. (Apiaceae) is a medicinal plant with a well-documented history in phytotherapy. The aim of the present work was to isolate isopimpinellin (5,8-methoxypsoralen; IsoP) from the fruit of this plant and evaluate its biological activity against selected tumor cell lines. The methanol extract obtained with the use of an accelerated solvent extraction (ASE) method was the most suitable for the quantitative analysis of coumarins in the A. majus fruit matrix. The coumarin content was estimated by RP-HPLC/DAD, and the amount of IsoP was found to be 404.14 mg/100 g dry wt., constituting 24.56% of the total coumarin fraction (1.65 g/100 g). This, along with the presence of xanthotoxin (368.04 mg/100 g, 22.36%) and bergapten (253.05 mg/100 g, 15.38%), confirmed A. majus fruits as an excellent source of these compounds. IsoP was isolated (99.8% purity) by combined liquid chromatography/centrifugal partition chromatography (LC/CPC) and tested for the first time on its antiproliferative activity against human colorectal adenocarcinoma (HT29, SW620), osteosarcoma (Saos-2, HOS), and multiple myeloma (RPMI8226, U266) cell lines. MTT assay results (96 h incubation) demonstrated a dose- and cell line-dependent decrease in cell proliferation/viability, with the strongest effect of IsoP against the Saos-2 cell line (IC50; 42.59 µM), medium effect against U266, HT-29, and RPMI8226 (IC50 = 84.14, 95.53, and 105.0 µM, respectively), and very weak activity against invasive HOS (IC50; 321.6 µM) and SW620 (IC50; 711.30 µM) cells, as well as normal human skin fibroblasts (HSFs), with IC50; 410.7 µM. The mechanistic study on the Saos-2 cell line showed that IsoP was able to reduce DNA synthesis and trigger apoptosis via caspase-3 activation. In general, IsoP was found to have more potency towards cancerous cells (except for HOS and SW620) than against healthy cells. The Selective Index (SI) was determined, underlining the higher selectivity of IsoP towards cancer cells compared to healthy cells (SI = 9.62 against Saos-2). All these results suggest that IsoP might be a promising molecule in the chemo-prevention and treatment of primary osteosarcoma.

Biological and metabolomics-guided isolation of tetrahydrofurofuran lignan from Croton spp. with antiproliferative activity against human melanoma cell line

The Croton genus (Euphorbiaceae) is recognized as a promising source for identifying bioactive compounds with antiproliferative activity. However, knowledge on the chemical composition and activity of Croton floribundus, Croton echinocarpus, and Croton zehntneri is limited. Thus, this study aimed to investigate the antiproliferative activity of these species on cells derived from tumoral breast, lung, and melanoma cells, and primary fibroblasts derived from human skin. Metabolomic strategies were applied via ultra-performance liquid chromatography coupled with high-resolution mass spectrometry and multivariate statistical analysis to target the main active compound. The C. floribundus leaf extract exhibited the highest activity, with an IC50 value lower than that of the reference drug – temozolomide – in the most responsive cell line – SK-MEL-147 – and in all the evaluated melanoma cell lines (SK-MEL-147, CHL-1 and WM-1366). Four tetrahydrofurofuran lignans were isolated for the first time from the most promising fraction of the C. floribundus extract. According to the metabolomic and multivariate statistical analyses, the isolated lignan epi-yangambin constituted the main antiproliferative compound against SK-MEL-147; furthermore, it exhibited selective antiproliferative activity for this cell line (IC50 = 13.09 μg/mL and selectivity index = 3.82; temozolomide, IC50 = 121.50 μg/mL) due to, at least in part, its ability to inhibit cell cycle progression at G2/M. This is especially relevant considering the high resistance of melanoma cells to available drugs. Thus, epi-yangambin can serve as a prototype for further antiproliferative investigations.

Cannabigerol and Cannabicyclol Block SARS-CoV-2 Cell Fusion.

The search for new active substances against SARS-CoV-2 is still a central challenge after the COVID-19 pandemic. Antiviral agents to complement vaccination are an important pillar in the clinical situation. Selected cannabinoids such as cannabigerol, cannabicyclol, cannabichromene, and cannabicitran from Cannabis sativa and synthetic homologues of cannabigerol and cannabicyclol were evaluated for effects on the cell viability of Vero cells (CC50 of cannabigerol and cannabicyclol 40 resp. 38 µM) and reduced virus entry of vesicular stomatitis pseudotyped viruses with surface-expressed SARS-CoV-2 spike protein at 20 µM. In addition to a reduction of pseudotyped virus entry, a titer reduction assay on Vero cells after preincubation of Wuhan SARS-CoV-2 significantly confirmed antiviral activity. Investigations on the molecular targets addressed by cannabigerol and cannabicyclol indicated that both compounds are inhibitors of SARS-CoV-2 spike protein-mediated membrane fusion, as could be shown by a virus-free reporter fusion inhibition assay (EC50 for cannabigerol 5.5 µM and for cannabicyclol 10.8 µM) and by monitoring syncytia formation in Vero reporter cells. Selectivity indices were calculated as 7.4 for cannabigerol and 3.5 for cannabicyclol. Systematic semisynthetic alterations of cannabigerol and cannabicyclol indicated that the side chains of both compounds do not contribute to the observed anti-membrane fusion activity.

X-ray Single-Crystal Analysis, Pharmaco-Toxicological Profile and Enoyl-ACP Reductase-Inhibiting Activity of Leading Sulfonyl Hydrazone Derivatives

Taking into consideration the growing resistance towards currently available antimycobacterials, there is still an unmet need for the development of new chemotherapeutic agents to combat the infectious agents. This study presents X-ray single-crystal analysis to verify the structure of leading sulfonyl hydrazone 3b, which has proven its potent antimycobacterial activity against Mycobacterium tuberculosis H37Rv with an MIC value of 0.0716 μM, respectively, low cytotoxicity, and very high selectivity indexes (SI = 2216), and which has been fully characterized by Nuclear Magnetic Resonance (NMR) and High-Resolution Mass Spectrometry (HRMS) methods. Furthermore, this study assessed the ex vivo antioxidant activity, acute and subacute toxicity, and in vitro inhibition capacity against enoyl-ACP reductase of hydrazones 3a and 3b, as 3a was identified as the second leading compound in our previous research. Compared to isoniazid, compounds 3a and 3b demonstrated lower acute toxicity for intraperitoneal administration, with LD50 values of 866 and 1224.7 mg/kg, respectively. Subacute toxicity tests, involving the repeated administration of a single dose of the test samples per day, revealed no significant deviations in hematological and biochemical parameters or pathomorphological tissues. The compounds exhibited potent antioxidant capabilities, reducing malondialdehyde (MDA) levels and increasing reduced glutathione (GSH). Enzyme inhibition assays of the sulfonyl hydrazones 3a and 3b with IC50 values of 18.2 µM and 10.7 µM, respectively, revealed that enoyl acyl carrier protein reductase (InhA) could be considered as their target enzyme to exhibit their antitubercular activities. In conclusion, the investigated sulfonyl hydrazones display promising drug-like properties and warrant further investigation.

Design of Selective PARP-1 Inhibitors and Antitumor Studies.

Designing selective PARP-1 inhibitors has become a new strategy for anticancer drug development. By sequence comparison of PARP-1 and PARP-2, we identified a possible selective site (S site) consisting of several different amino acid residues of α-5 helix and D-loop. Targeting this S site, 140 compounds were designed, synthesized, and characterized for their anticancer activities and mechanisms. Compound I16 showed the highest PARP-1 enzyme inhibitory activity (IC50 = 12.38 ± 1.33 nM) and optimal selectivity index over PARP-2 (SI = 155.74). Oral administration of I16 (25 mg/kg) showed high inhibition rates of Hela and SK-OV-3 tumor cell xenograft models, both of which were higher than those of the oral positive drug Olaparib (50 mg/kg). In addition, I16 has an excellent safety profile, without significant toxicity at high oral doses. These findings provide a novel design strategy and chemotype for the development of safe, efficient, and highly selective PARP-1 inhibitors.

In Silico Drug Repurposing Uncovered the Antiviral Potential of the Antiparasitic Drug Oxibendazole Against the Chikungunya Virus.

Chikungunya virus (CHIKV) has been reported in over 120 countries and is the causative agent of Chikungunya fever. The debilitating nature of this disease, which can persist months to years after acute infection, drastically impacts the quality of life of patients. Yet, specific antivirals are lacking for the treatment of this disease, which makes the search for new drugs necessary. In this context, the nsP2 protease emerges as an attractive therapeutic target, and drug repurposing strategies have proven to be valuable. Therefore, we combined in silico and in vitro methods to identify known drugs as potential CHIKV nsP2 protease inhibitors with antiviral properties within DrugBank. Herein, we developed a hybrid virtual screening pipeline comprising pharmacophore- and target-based screening, drug-like, and pharmaceutical filtering steps. Six virtual hits were obtained, and two of them, capecitabine (CPB) and oxibendazole (OBZ), were evaluated against CHIKV replication in Vero cells. CPB did not present antiviral activity, whereas OBZ inhibited the replication of two different strains of CHIKV, namely, 181-25 (Asian genotype) and BRA/RJ/18 (clinical isolate from ECSA genotype). OBZ showed potent antiviral activity against the CHIKV BRA/RJ/18 (EC50 = 11.4 μM) with a high selectivity index (>44). Analogs of OBZ (albendazole, fenbendazole, and mebendazole) were also evaluated, but none exhibited anti-CHIKV activity, and further, their stereoelectronic features were analyzed. Additionally, we observed that OBZ acts mainly at post-entry steps. Hence, our results support further in vivo studies to investigate the antiviral potential of OBZ, which offers a new alternative to fight CHIKV infections.

Naphthoquinone-Quinolone Hybrids with Antitumor Effects on Breast Cancer Cell Lines-From the Synthesis to 3D-Cell Culture Effects.

Breast cancer stands as one of the foremost cause of cancer-related deaths globally, characterized by its varied molecular subtypes. Each subtype requires a distinct therapeutic strategy. Although advancements in treatment have enhanced patient outcomes, significant hurdles remain, including treatment toxicity and restricted effectiveness. Here, we explore the anticancer potential of novel 1,4-naphthoquinone/4-quinolone hybrids on breast cancer cell lines. The synthesized compounds demonstrated selective cytotoxicity against Luminal and triple-negative breast cancer (TNBC) cells, which represent the two main molecular types of breast cancer that depend most on cytotoxic chemotherapy, with potency comparable to doxorubicin, a standard chemotherapeutic widely used in breast cancer treatment. Notably, these derivatives exhibited superior selectivity indices (SI) when compared to doxorubicin, indicating lower toxicity towards non-tumor MCF10A cells. Compounds 11a and 11b displayed an improvement in IC50 values when compared to their precursor, 1,4-naphthoquinone, for both MCF-7 and MDA-MB-231 and a comparable value to doxorubicin for MCF-7 cells. Also, their SI values were superior to those seen for the two reference compounds for both cell lines tested. Mechanistic studies revealed the ability of the compounds to induce apoptosis and inhibit clonogenic potential. Additionally, the irreversibility of their effects on cell viability underscores their promising therapeutic utility. In 3D-cell culture models, the compounds induced morphological changes indicative of reduced viability, supporting their efficacy in a more physiologically relevant model of study. The pharmacokinetics of the synthesized compounds were predicted using the SwissADME webserver, indicating that these compounds exhibit favorable drug-likeness properties and potential as antitumor agents. Overall, our findings underscore the promise of these hybrid compounds as potential candidates for breast cancer chemotherapy, emphasizing their selectivity and efficacy.

Novel naphthoquinones as potent aromatase inhibitors: Synthesis, anticancer, and in silico studies

A set of 26 naphthoquinone derivatives (3-28) were synthesized by nucleophilic substitution or Michael addition of various amines with 1,4-naphthoquinones and were investigated for their aromatase inhibitory and anticancer activities. The 1,4-naphthoquinone derivatives with amino substituents (14-16 and 24) and the N-alkylated products (25-28) showed promising aromatase inhibitory activity (IC50 = 0.006–2.6 µM). Interestingly, 2-((4-aminophenyl)amino)-3-chloronaphthalene-1,4-dione 14 was noted as a highly potent aromatase inhibitor (IC50 = 6 nM) possessing preferable selective anticancer effect against the breast cancer T47D cell line (IC50: cytotoxic T47D = 24.3 µM, non-cytotoxic to MRC-5 normal cell line, selective index > 6.9). Findings from molecular docking study also suggested that the hydrogen bond formation with Asp309 as well as the pi-sulfur interaction with Met374 residues may be essential for a striking inhibitory effect of the most potent compound 14. Moreover, the in silico drug-likeness prediction indicated that all active naphthoquinone-based compounds are drug-like molecules with potential to be further developed as dual-action anticancer agents for breast cancer management.