Selectivity Index Research Articles

Derivatives of (–)-Cytisine with Thiourea Fragment. Synthesis and Antiviral Activity

New derivatives of the quinolizidine alkaloid, (–)-cytisine, with a substituted 2-pyridone ring and a thiourea moiety in the bispidin fragment of the molecule were synthesized. The ability of the synthesized cytisine-containing thioureas to inhibit the reproduction of human parainfluenza virus type 3 was assessed. It was found that the derivatives obtained by the reaction of benzoyl or phenyl isothiocyanate with (–)-cytisine, as well as its 9-bromo or 9,11-derivative, effectively suppress the reproduction of human parainfluenza virus type 3 (their selectivity indices are 56, 58 and 95, respectively), which confirms the promise of the chosen approach to synthetic modifications of the alkaloid (–)-cytisine in order to obtain effective antiviral agents on its basis.

In Vitro and In Vivo Antitumor Activity of Lophocereus marginatus (DC.) S. Arias & Terrazas Endophytic Aspergillus versicolor and Metarhizium anisopliae Extracts Against the Murine Lymphoma L5178Y-R

Cancer belongs to a group of diseases characterized by uncontrolled cell growth. The search for new effective treatments for cancer has led to the discovery of different molecules from plants, bacteria, and fungi with pharmacological use. Plant endophytic fungi are large producers of metabolites with antitumor properties. We aimed to evaluate the in vitro and in vivo antitumor potential of extracts from Lophocereus marginatus endophytic fungi. We obtained ethyl acetate and hexane extracts from the L. marginatus endophytes Metarhizium anisopliae and Aspergillus versicolor and evaluated their antitumor activity against murine L5178Y-R lymphoma cells and human peripheral blood mononuclear cells, using the 3-(4,5-dimethylthiazol-2-yl)-2-diphenyltetrazolium bromide reduction colorimetric technique. M. anisopliae and A. versicolor ethyl acetate extracts showed IC50 values of 9.168 ± 1.21 μg/mL and 13.51 ± 1.62, respectively, and selectivity indices > 30. We also observed that the maximum tolerated dose (100 mg/kg) of ethyl acetate extracts and the vehicle in BALB/c mice did not cause hepatotoxicity. In addition, we evaluated the effects of ethyl acetate extracts on survival and tumor volume in the L5178Y-R lymphoma tumor model. An increase in survival (17 d) was observed in mice treated with A. versicolor extract. Furthermore, it did not increase tumor volume during 10 d, as compared with the control groups without treatment, vehicle, and M. anisopliae extract, which had a maximum survival of 10 d. A. versicolor ethyl acetate extract showed in vitro and in vivo antitumor activity against lymphoma L5178Y-R, increasing mice survival.

Diels–Alder Adducts of <i>N</i>-Substituted 2-Pyridones with Maleinimides. Synthesis and Antiviral Activity

Adducts of N-substituted 2-pyridones [pyridine-2(1H)-ones] and N-substituted maleic acid imides were synthesized under thermal conditions of the Diels–Alder reaction with yields from 68 to 97%. Cytotoxicity and antiviral activity of the obtained compounds were studied using a model of adenovirus infection [human adenovirus type 5 (AdV5)] in MA-104 cell culture. It was shown that the synthesized adducts have low toxicity and medium antiviral activity. Only 9-hexyl-2-phenyl-3a,4,7,7a-tetrahydro-1H-4,7-(epiminomethano)isoindole-1,3,8-trione has the most pronounced viral inhibitory properties with a selectivity index of 7.

Synthesis, antiviral activity against wild-type SARS-CoV-2 and molecular docking studies of new aryl(1,2-dithiolo[3,4-c]quinolin-1-ylidene)amines

Unlike most attempts to find compounds with activity against SARS-CoV-2 aimed at reusing approved drugs, our goal was to find compounds with antiviral activity among the 1,2-dithioloquinoline derivatives we synthesized. These compounds exhibit pleiotropic effects, having a novel structure compared to known pharmaceuticals. In this work, we diversified the structure of 1,2-dithioloquinoline by introducing various substituents (chlorine atom, ether, amide, sulfonamide groups, pharmacophore heterocycles) into different positions of this tricyclic framework. Using docking with further quantum chemical post-processing of calculations of the created virtual library of 404 structures, more than ten compounds of the aryl(4,4-dimethyl-4,5-dihydro-1H-[1,2]dithiolo[3,4-c]quinoline-1-ylidene)amine series were discovered, synthesized and experimentally studied. The bioactive screening of newly synthesized compounds revealed that six of them demonstrate suppression of SARS-CoV-2 replication in Vero E6 cell culture in the micromolar range of EC50 values (from 0.27 to 98.48 μM). The best compound, in the structure of which fragments of tricyclic dithioloquinoline and streptocide are combined, demonstrated a highest ability to protect Vero E6 cells from SARS-CoV-2 with EC50 = 0.27 μM, as well as low cytotoxicity with a selectivity index SI > 370, exceeding all reference values compounds used in the study (remdesivir, GC376, ML188).

Characterization and Bioactive Metabolite Profiling of Streptomyces sp. Y009: A Mangrove-Derived Actinomycetia with Anticancer and Antioxidant Potential

Microorganisms from poorly explored environments are promising sources for the development of novel drugs. In our continuous efforts to screen for mangrove actinomycetes that produce metabolites with potential pharmaceutical applications, Streptomyces sp. Y009 was isolated from mangrove sediments in Guangxi, China. The phenotypic, physiological, biochemical, and phylogenetic characteristics of this strain were investigated. Analysis of phylogenetic and 16S rRNA gene sequences showed that it had the highest sequence similarity to Streptomyces thermolilacinus NBRC 14274 (98.95%). Further, the Y009 extract exhibited antioxidant activity, as indicated by DPPH and superoxide dismutase assays. The extract showed broad-spectrum and potent anticancer potential against six human cancer cell lines, with IC50 values ranging from 5.61 to 72.15 μg/mL. Furthermore, the selectivity index (SI) demonstrated that the Y009 extract exhibited less toxicity toward normal cell lines in comparison to the lung cancer cell line (A549) and hepatoma cell line (HepG2). GC–MS analysis revealed that the extract contained some biologically important secondary metabolites, mainly cyclic dipeptides and esters, which might be responsible for the antioxidant and anticancer properties. 3-Isobutylhexahydropyrrolo[1,2-a]pyrazine-1,4-dione (28.32%) was the major chemical compound available in the extract. The effect on cancer cells was then confirmed using nuclear staining and in silico docking. This study suggests that further exploration of the bioactive compounds of the newly isolated strain may be a promising approach for the development of novel chemopreventive drugs.

Curcumin Derivatives in Medicinal Chemistry: Potential Applications in Cancer Treatment

Curcumin, a naturally occurring compound found in the rhizome of Curcuma plants, particularly in turmeric (Curcuma longa L.), exhibits a broad range of biological activities, including anti-inflammatory, antioxidant, and anticancer properties. Curcumin has demonstrated effectiveness in inhibiting tumor growth, arousing interest for its potential in treating various cancers, such as breast, lung, prostate, and brain cancers. However, the clinical application of curcumin is limited due to its low chemical stability, poor water solubility, and low bioavailability. In response to these challenges, structural modifications of curcumin have been explored to improve its pharmacological properties, including enhanced anticancer selectivity index and bioavailability. This review highlights promising chemical modifications of curcumin that could lead to the development of more effective anticancer therapies. By functionalizing the parent curcumin molecule, researchers aim to create more stable and bioavailable compounds with enhanced therapeutic potential, making curcumin derivatives promising candidates for medical applications.

A Comprehensive Evaluation of a Coumarin Derivative and Its Corresponding Palladium Complex as Potential Therapeutic Agents in the Treatment of Gynecological Cancers: Synthesis, Characterization, and Cytotoxicity

Background: The aim of this research is the synthesis and characterization of coumarin-palladium complex and the investigation of the cytotoxicity of both the ligand and the complex. Methods: The palladium( II) complex (CC) was obtained in the reaction between (E)-3-(1-((4-hydroxy-3-methoxyphenyl)amino)ethylidene)-2,4-dioxochroman-7-yl-acetate (CL) and potassium-tetrachloropalladate(II) and characterized using IR and NMR spectra, experimentally and theoretically. Cytotoxicity of CL and CC were determined for human cervical carcinoma HeLa, ovarian cancer A2780, hormone dependent breast cancer MCF7, and colorectal cancer HCT116 lines. The interaction of investigated compounds with HSA was followed by spectrofluorimetric method. The binding mechanism in the active pocket was assessed via molecular docking simulations. Results: A low mean absolute error between experimental and theoretical data proved that the optimized structure corresponded to the experimental one. Both compounds showed a satisfactory selectivity index towards neoplastic cells. The binding affinity of tested compounds to the HSA were confirmed. The molecular docking showed a much lower change in the Gibbs free energy of binding for CC compared to CL. Conclusions: The obtained results revealed that CL and CC exhibit significant effects on several cancer cell lines and good binding properties to HSA, while molecular docking discovered that CC has the most pronounced activity against alpha-fetoprotein.

Discovery of novel fused-heterocycle-bearing diarypyrimidine derivatives as HIV-1 potent NNRTIs targeting tolerant region I for enhanced antiviral activity and resistance profile

As an important part of anti-AIDS therapy, HIV-1 non-nucleoside reverse transcriptase inhibitors are plagued by resistance and toxicity issues. Taking our reported XJ-18b1 as lead compound, we designed a series of novel diarypyrimidine derivatives by employing a scaffold hopping strategy to discover potent NNRTIs with improved anti-resistance properties and drug-like profiles. The most active compound 3k exhibited prominent inhibitory activity against wild-type HIV-1 (EC50 = 0.0019 μM) and common mutant strains including K103 N (EC50 = 0.0019 μM), L100I (EC50 = 0.0087 μM), E138K (EC50 = 0.011 μM), along with low cytotoxicity and high selectivity index (CC50 = 21.95 μM, SI = 11478). Additionally, compound 3k demonstrated antiviral activity against HIV-2 with EC50 value of 6.14 μM. The enzyme-linked immunosorbent assay validated that 3k could significantly inhibit the activity of HIV-1 reverse transcriptase (IC50 = 0.025 μM). Furthermore, molecular dynamics simulation studies were performed to illustrate the potential binding mode and binding free energy of the RT-3k complex, and in silico prediction revealed that 3k possessed favorable drug-like profiles. Collectively, 3k proved to be a promising lead compound for further optimization to obtain anti-HIV drug candidates.

Discovery of novel thiosemicarbazone-acridine targeting butyrylcholinesterase with antioxidant, metal complexing and neuroprotector abilities as potential treatment of Alzheimer's disease: In vitro, in vivo, and in silico studies

Inhibition of cholinesterases, combined with antioxidant activity, metal-chelating capacity, and neuroprotection, is recognized as an effective multitarget therapy for the treatment of Alzheimer's disease (AD). Based on our in-house thiosemicarbazone-acridine compounds, this study recognized these derivatives as possible multi-target-directed ligand (MTDL). Initial screening against cholinesterases identified CL-01, which exhibited a promising IC50 value of 0.71 μM against butyrylcholinesterase (BChE). Twelve new derivatives were designed based on CL-01 aiming to retain the BChE inhibitory activity while incorporating a MTDL profile, including antioxidant properties and metal-complexing abilities. Among the new derivatives, CL-13 maintained a good BChE inhibition (IC50 = 1.15 μM) with improved selective index against acetylcholinesterase (SI = 9.2). The acridine nucleus was important for the activity, as its saturated tetrahydroacridine analogue (TA-01) showed a decrease in cholinesterases inhibition potencies and altered the mode of inhibition, revealing for the first time distinct functional roles for the two nuclei. Moreover, CL-13 emerged as a promising lead compound, demonstrating interesting antioxidant activity (DPPH EC50 = 47.01 μM), chelating capacity of biometals involved in Aβ aggregation and/or oxidative stress, and a lack of neurotoxicity at 50 μM in SH-SY5Y cells. It also exhibited neuroprotective effects in an in vitro oxidative stress model induced by H2O2. Finally, in vivo experiments confirmed that CL-13 effectively reversed scopolamine-induced cognitive impairment, without affecting locomotor activity in the mice.

Design, in silico studies and biological evaluation of novel chalcones tethered triazolo[3,4-a]isoquinoline as EGFR inhibitors targeting resistance in non-small cell lung cancer

A novel series of six [1,2,4]triazolo[3,4-a]isoquinolin-3-yl)-3-(1,3-diphenyl-1H-pyrazol-4-yl)prop-2-en-1-ones (3a–3f) was designed and synthesized. They were characterized based on spectral and elemental analyses. In silico studies were also committed to provide insights and a better understanding of their structural features. The six compounds were screened for their antiproliferative activity using the MTT assay against five human cancer cell lines, namely, A549, HCT116, PC3, HT29, and MCF-7 in parallel with the non-cancerous human lung cell line WI-38. The results showed that 3e and 3f have potential cytotoxic activities, especially on A549 cells with IC50 = 2.3 µM and 1.15 µM, respectively. Meanwhile, they recorded a minimal cytotoxic effect on WI-38 cells. Concerning the molecular mechanism of action, the present study showed the inhibitory effect of the six compounds against total EGFR. The most potent EGFR inhibitors were 3e and 3f with IC50 = 0.031 µM and 0.023 µM, respectively. The selectivity index of 3f for EGFRT790M was 1.81 times more selective than that of lapatinib. In addition, 3e and 3f initiated cell cycle arrest at the G2/M and pre-G1 phases along with the downregulation of anti-apoptotic protein Bcl2 and the upregulation of pro-apoptotic proteins: p53, Bax, and caspases 3, 8, and 9. Further studies are recommended to evaluate animal models’ promising anticancer activity and molecular mechanism of triazolo[3,4-a]isoquinoline derivatives 3e and 3f.

The proteinuria selectivity index value predicts the remission of IgA nephropathy: a retrospective cohort study

IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide and leads to end-stage kidney disease. The proteinuria selectivity index (PSI) has been used to assess the prognosis in nephrotic syndrome, but its predictive value in patients with IgAN remains unclear. This single-center retrospective cohort study included patients who diagnosed with IgAN between March 2012 and March 2020. The PSI was calculated at the time of kidney biopsy. Patients were followed up from the time of kidney biopsy to kidney replacement therapy, death, transfer to another facility, or study completion. Ninety-four patients with a median age of 51 years were enrolled and divided according to the cutoff value of PSI determined by the receiver operating characteristic curve analysis into low-PSI (PSI <0.243, n = 39) and high-PSI groups (PSI ≥0.243, n = 55). The median follow-up duration was 70 months. Rates of remission of proteinuria and survival without a two-fold increase in serum creatinine were significantly better in the low-PSI group (both p < 0.01, log-rank test). Cox regression analysis showed that a low PSI was significantly associated with an increased likelihood of remission of proteinuria and hematuria (hazard ratio [HR] 1.96; 95% confidence interval [CI] 1.02–3.85 and HR 1.75; 95% CI 1.01–3.13, respectively), and a decreased risk of a two-fold increase in serum creatinine (HR 0.10; 95% CI 0.01–0.81). In conclusion, The PSI could have the potential to support the assessment of the prognosis of IgAN, in addition to established prognostic markers, by reflecting the overall glomerular permeability.

Novel synthetic UV screen compounds inspired in mycosporine-like amino acids (MAAs): Antioxidant capacity, photoprotective properties and toxicity

The combination of environmental stress on the ozone layer, climate change and a greater sun exposure due to outdoor habits has led to an increase in skin cancer cases and other health issues related with UV radiation. Researchers are searching for new alternative UV filters that could protect our skin from the deleterious effects of UV radiation while also presenting low toxicity and biodegradable character (unlike the UV filters currently available in the market). In this work, two compounds inspired in the natural oxo-mycosporine-like amino acids (MAAs) have been synthesized and their antioxidant and photoprotective properties, as well as their in vitro and in vivo toxicity effects were evaluated. Both compounds featured a strong UV-B absorption together with a high antioxidant capacity, close to 50 μmol TE g−1 DW in the ABTS assay. Compound 1 presented an absorption peak at 285–300 nm, whereas compound 2 showed a wider band with a peak around 295–305 nm and two shoulders at 318 and 342 nm. The addition of 5 % of compound 2 to galenic formulas increased the photoprotection, reaching SPF values of 4. Both compounds were stable under UV radiation exposure. Regarding toxicity, the synthetic compounds did not show cytotoxic activity against healthy human cell lines or significant toxicity over zebrafish embryos. Compound 1 showed a complete lack of toxicity over zebrafish, although compound 2 showed slight, not-significant effects on viability, hatching, pericardial stability or body axis formation over 5 mg mL−1. Moreover, compound 1 presented relatively antitumoral activities against HCT-116 cells (selective index:1.49). The relevant antioxidant and photoprotective ability together with the great advantage provided by the reduced toxicity to health cells or zebrafish embryos, make these compounds promising candidates to be exploited as functional ingredients with specific applications in the biotechnological or pharma sector.

Ionic liquid promoted facile one-pot synthesis of phenothiazine-thiazolidin-4-ones as potent antitubercular agents via mycobacterial ATP synthase inhibition

The mycobacterial ATP synthase is responsible for the optimal growth, metabolism and viability of mycobacteria, establishing it as a validated target for the development of anti-TB therapeutics. Herein, we report the facile and efficient one-pot three component synthesis of 2-(10H-phenothiazin-3-yl)-3-substituted thiazolidin-4-one derivatives by using ionic liquid, 1-butyl-3-methylimidazolium bromide [Bmim]Br and their inhibitory potency against mycobacterium tuberculosis H37Rv strain (ATCC-27294). Compound T27 exhibited the highest inhibition activity with an MIC of 0.78 μg/mL, which is twofold and fourfold superior (in terms of the MIC values) to the standard first-line TB drugs isoniazid (MIC: 1.56 μg/mL) and pyrazinamide (MIC: 3.12 μg/mL) respectively. Two other compounds (T25 and T30) are equipotent as the isoniazid. The SAR studies revealed that insertion of 1,2,3-traizole and thiozolidine-2-one rings enhance the anti-TB activity in most of the tested compounds. Also, compound T27 was screened for mycobacterial ATP synthase inhibition activity and it exhibited an IC50 of 0.735 µM in M. smegmatis IMVs. Further, toxicity evaluation against VERO cell lines confirmed null cytotoxicity (selectivity index > 70) of the potent analogues. The title compounds are highly specific towards to the M. tb strain, i.e., most of the compounds exhibited moderate inhibitory potency against the tested bacterial strains (MIC ≥ 6.25 μg/mL). In addition, molecular docking was employed against the active site of the ATP synthase enzyme to validate the binding mechanism and in vitro activity profile of the phenothiazine derivatives. Furthermore, in silico ADME and pharmacokinetic parameters’ prediction indicated good oral bioavailability.

Structure Activity Relationship of Diarylidenecyclopentanone Derivatives as Potent Antiplasmodial Agents

AbstractIn our efforts to design mono‐carbonyl analogues of curcumin with potential antiplasmodial activity, diarylidenecyclopentanone (DACP) derivatives, Ia–Iu and II–V, have been synthesized and characterized using 1H NMR, 13C NMR, IR, UV–Vis, and mass spectrometry. Structure of one of these DACPs has been verified by single crystal XRD. At the outset, all 25 DACPs were first screened at 12.5 µM for their in vitro antiplasmodial activity against the chloroquine (CQ)‐sensitive Pf3D7. The three most potent compounds (In, It, and Ik) were further tested at &lt;10 µM concentrations against Pf3D7, PfINDO (CQ resistant), and PfMRA‐1240 (Artemisinin resistant) strains for determination of their IC50s and resistance indices. The drug profile of the DACPs was found to be very promising, with the most active compound It (IC50 1.39 µM against PfINDO) showing a selectivity index of ∼17 tested using HUH‐7 and HEK‐293T mammalian cell lines. Molecular docking studies with Pf pyridoxal synthase showed a good correlation between docking scores of DACPs and in vitro antiplasmodial activity. Further, high conformity with Lipinski's parameters indicates that these DACPs are promising antiplasmodial lead compounds.

New vatalanib analogs: Design, synthesis, in silico study and biological evaluation for anticancer activity

In our attempts to improve pharmacokinetics and pharmacodynamics characters of vatalanib, four strategies of the drug design were applied to design and synthesis new quinoxaline based vatalanib analogs. Antiproliferative activities of the synthesized compounds were investigated against two tumor cell lines (HepG2 and HCT‐116) using vatalanib as a positive control. The new candidates showed promising anticancer activity against two tested cancer cell lines with IC50 values ranging from 6.04 ± 0.19 to 100.15 ± 3.26 µM, in particular compounds 11b and 11c which were more potent than vatalanib. The most potent was the 4-benzoylquinoxaline derivative 11b (IC50 = 6.04 ± 0.19 µM and 15.58 ± 0.58 µM) compared to vatalanib (IC50 of 25.27 ± 0.84 µM and 43.91 ± 1.64 µM) against HepG2 and HCT116, respectively. The selectivity indices of 11b were found to be approximately 14 and 5 towards HepG2 and HCT116, respectively. While vatalanib showed selectivity indices of about 5 and 3 towards HepG2 and HCT116, respectively. The most promising compound 11b was further investigated in HepG‐2 cells for its apoptotic effect, cell cycle arrest and in vitro VEGFR-2 inhibitory activity as the main mechanisms of cell death. It was found that 11b can induce apoptosis and arrest the cell cycle at the at G1 phase in addition to, compound 11b showed effective inhibition of VEGFR-2 with IC50 of 0.918 ± 0.033 µM compared to vatalanib (IC50 of 0.265 ± 0.009 µM). Deep computational studies were created for the designed compounds including molecular docking, physicochemical properties, profiling pharmacokinetics, ADMET studies, and toxicity predictions to evaluate the prospective drug candidates. The results of the docking study were consistent with biological testing, furthermore, in silico ADMET study revealed the superior pharmacokinetics characters of the new candidates over vatalanib. So, the current work suggests that the 4-benzoylquinoxaline-1-yl-acetamide derivatives, especially 11b, can serve as lead molecules for development of new effective anticancer drugs.

Novel benzenesulfonamide-aroylhydrazone conjugates as carbonic anhydrase inhibitors that induce MAPK/ERK-mediated cell cycle arrest and mitochondrial-associated apoptosis in MCF-7 breast cancer cells

A series of novel 4-alkylthio-2-chloro-5-[(2-arylmethylidene)hydrazinecarbonyl]benzenesulfonamide derivatives 3–22 were synthesized and evaluated for their inhibitory activity against human carbonic anhydrase isozymes hCA I, hCA II, hCA IX, and hCA XII. These compounds showed varying degrees of activity against the studied isoenzymes. However, the importance of substituent choice in designing potent carbonic anhydrase inhibitors is highlighted by the strong inhibition profiles of compounds 3 and 10 against hCA IX and the low average KI values for compounds 9 and 10 (134 nM and 77 nM, respectively). All the synthesized compounds were evaluated for their antiproliferative activity toward HeLa, HCT-116, and MCF-7 cell lines. Compounds 9 and 19 exhibited significant activity, particularly against the MCF-7 cell line (IC50 values of 4 μM and 6 μM, respectively). Notably, compound 9 demonstrated a high selectivity index (SI = 8.2) for MCF-7 cells. The antiproliferative effects of compounds 9 and 19 were linked to the induction of cell cycle arrest and apoptosis via the mitochondrial pathway and involved the activation of the MAPK/ERK signaling pathway. Inhibition of MAPK/ERK activity reduced the compounds’ ability to induce cell cycle arrest and apoptosis, indicating the critical role of this pathway. These findings suggest that compounds 9 and 19 are promising candidates for further development as specific and potent anticancer agents targeting the MAPK/ERK pathway.

Insight into the Natural Biomolecules (BMs): Promising Candidates as Zika Virus Inhibitors.

Zika virus (ZIKV) is among the relatively new infectious disease threats that include SARS-CoV-2, coronavirus, monkeypox (Mpox) virus, etc. ZIKV has been reported to cause severe health risks to the fetus. To date, satisfactory treatment is still not available for the treatment of ZIKV infection. This review examines the last five years of work using natural biomolecules (BMs) to counteract the ZIKV through virtual screening and in vitro investigations. Virtual screening has identified doramectin, pinocembrin, hesperidins, epigallocatechin gallate, pedalitin, and quercetin as potentially active versus ZIKV infection. In vitro, testing has shown that nordihydroguaiaretic acid, mefloquine, isoquercitrin, glycyrrhetinic acid, patentiflorin-A, rottlerin, and harringtonine can reduce ZIKV infections in cell lines. However, in vivo, testing is limited, fortunately, emetine, rottlerin, patentiflorin-A, and lycorine have shown in vivo anti- ZIKV potential. This review focuses on natural biomolecules that show a particularly high selective index (>10). There is limited in vivo and clinical trial data for natural BMs, which needs to be an active area of investigation. This review aims to compile the known reference data and discuss the barriers associated with discovering and using natural BM agents to control ZIKV infection.

Structure activity relationships of antischistosomal N-phenylbenzamides by incorporation of electron-withdrawing functionalities

For the adult Schistosoma mansoni flatworm pathogen, we report further structure activity relationships (SAR) of 19 N-phenylbenzamide analogs. Our previous SAR studies, designed by selecting representative substituents from the Craig plot, identified 9 and 11 which possessed electron-withdrawing groups that benefited potency. This study sought to enhance the potency of this chemotype by incorporating other electron-withdrawing functionalities not studied previously and to overcome the potential pharmacokinetic liabilities associated with the high lipophilicity of frontrunner compounds. Compared to the most potent compound, 9 (EC50 = 80 nM), from our previous work, the most potent compounds in the current study (32 (EC50 = 1.17 µM), 34 (EC50 = 1.64 µM) and 38 (EC50 = 1.16 µM)) were less active although they retained single digit micromolar potency. Furthermore, compound 38 generated a CC50 value of > 20 µM in counter toxicity screens using HEK 293 cells, translating to a wide selectivity index of > 17.

Uncovering the therapeutic potential of green pea waste in breast cancer: a multi-target approach utilizing LC-MS/MS metabolomics, molecular networking, and network pharmacology

Background Pisum sativum(PS) is a universal legume plant utilized for both human and animal consumption, particularly its seeds, known as green peas. The processing of PS in food industries and households produces a significant amount of waste that needs to be valorized.MethodsIn this study, the metabolite profiles of the 70% ethanolic extracts of PS wastes, namely peels (PSP) and a combination of leaves and stems (PSLS), were investigated by liquid chromatography-electrospray ionization-quadrupole time-of-flight tandem mass spectrometry (LC-ESI-QTOF-MS/MS) followed by molecular networking.ResultsDifferent classes of metabolites were identified, being flavonoids and their derivatives, along with phenolic acids, the most abundant categories. Additionally, a comprehensive network pharmacology strategy was applied to elucidate potentially active metabolites, key targets, and the pathways involved in cytotoxic activity against breast cancer. This cytotoxic activity was investigated in MCF-7 and MCF-10a cell lines. Results revealed that PSLS extract exhibited a potent cytotoxic activity with a good selectivity index (IC50 = 17.67 and selectivity index of 3.51), compared to the reference drug doxorubicin (IC50 = 2.69 µg/mL and selectivity index of 5.28). Whereas PSP extract appeared to be less potent and selective (IC50 = 32.92 µg/mL and selectivity index of 1.62). A similar performance was also observed for several polyphenolics isolated from the PSLS extract, including methyl cis p-coumarate, trans p-coumaric acid, and liquiritigenin/ 7-methyl liquiritigenin mixture. Methyl cis p-coumarate showed the most potent cytotoxic activity against MCF-7 cell line and the highest selectivity (IC50 = 1.18 µg/mL (6.91 µM) and selectivity index of 27.42). The network pharmacology study revealed that the isolated compounds could interact with several breast cancer-associated protein targets including carbonic anhydrases 1, 2, 4, 9, and 12, as well as aldo-keto reductase family 1 member B1, adenosine A3 receptor, protein tyrosine phosphatase non-receptor type 1, and estrogen receptor 2.ConclusionThe uncovered therapeutic potential of PSLS and its metabolite constituents pave the way for an efficient and mindful PS waste valorization, calling for further in-vitro and in-vivo research.Graphical

Synthesis and Antitumour Activity of Hybrid Compounds Based on 4-Aminophenylarsonic Acid and Spatially Hindered Phenols.

One of the main modern approaches to the creation of effective drugs is the design of new biologically active substances containing two or more pharmacophore groups in their structure. In recent years, there have been many publications on the synthesis and study of biological activity, including antitumour activity, of new organo-arsenic compounds. It is known that spatially hindered phenols can also have antitumor activity, so the synthesis and study of hybrid compounds based on organo-arsenic compounds and spatially hindered phenols is a relevant area of research. In this work, the modification of 4-aminophenylarsonic acid with 3,5-di-tert-butyl-4-hydroxybenzylacetate was carried out. In contrast to a similar transformation of 2-aminophenylarsonic acid, in this case it was possible to obtain both mono- and di-benzyl derivatives of the acid. Using the Zandmeyer method, the oxime isatin containing an arsonic acid fragment in the fifth position of the heterocycle was synthesised. Azo derivatives containing fragments of para-aminophenylarsonic acid and sterically hindered phenols were obtained. 4-((3,5-Di-tert-butyl-2-hydroxyphenyl)diazenyl)phenylarsonic acid was isolated in pure form. At the same time, it was found that the reaction of the diazonium azo salt of 4-aminophenylarsonic acid with 2-hydroxymethyl-4-tert-butylphenol proceeds in two directions. In addition to the classical diazotisation reaction at the 6-position of 2-hydroxymethyl-4-tert-butylphenol, a diazotisation accompanied by a dehydroxymethylation process occurs. The obtained compounds showed cytotoxic activity against human tumor cell lines M-HeLa (cervical epithelioid carcinoma) and HuTu 80 (duodenal adenocarcinoma cells). The most promising is the sodium salt of 4-((3,5-di-tert-butyl-2-hydroxyphenyl)diazenyl)phenylarsonic acid, which is superior to Tamoxifen and 5-fluorouracil in terms of selectivity index towards M-HeLa and HuTu 80 cells.