Design, synthesis and in vitro validation of bivalent binders of SARS-CoV-2 spike protein: Obeticholic, betulinic and glycyrrhetinic acids as building blocks

Bioorganic & Medicinal Chemistry, Год журнала: 2025, Номер 121, С. 118124 - 118124

Опубликована: Фев. 18, 2025

Язык: Английский

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Design, synthesis, and in vitro and in silico study of 1-benzyl-indole hybrid thiosemicarbazones as competitive tyrosinase inhibitors

RSC Advances, Год журнала: 2024, Номер 14(39), С. 28524 - 28542

Опубликована: Янв. 1, 2024

Developing new anti-tyrosinase drugs seems crucial for the medical and industrial fields since irregular melanin synthesis is linked to resurgence of several skin conditions, including melanoma, browning fruits vegetables. A novel series N-1 C-3 substituted indole-based thiosemicarbazones 5(a-r) are synthesized further analyzed their inhibition potential against tyrosinase enzyme through

Язык: Английский

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In Vitro and In Vivo Biological Evaluation of Indole-thiazolidine-2,4-dione Derivatives as Tyrosinase Inhibitors

Molecules, Год журнала: 2023, Номер 28(22), С. 7470 - 7470

Опубликована: Ноя. 7, 2023

Tyrosinase is an important rate-limiting enzyme in melanin biosynthesis. To find potential tyrosinase inhibitors with anti-melanogenic activity, a series of indole-thiazolidine-2,4-dione derivatives 5a~5z were synthesized by incorporating indole thiazolidine-2,4-dione into one compound and assayed for their biological activities. All compounds displayed inhibitory activities 5w had the highest anti-tyrosinase activity IC50 value 11.2 μM. Inhibition kinetics revealed as mixed-type inhibitor. Fluorescence quenching results indicated that quenched fluorescence static process. CD spectra 3D suggested binding could change conformation microenvironment tyrosinase. Molecular docking also represented between Moreover, inhibit melanogenesis both B16F10 cells zebrafish model. Therefore, serve inhibitor activity.

Язык: Английский

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Naphthyl-Substituted Indole and Pyrrole Carboxylic Acids as Effective Antibiotic Potentiators—Inhibitors of Bacterial Cystathionine γ-Lyase

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(22), С. 16331 - 16331

Опубликована: Ноя. 15, 2023

Over the past decades, problem of bacterial resistance to most antibiotics has become a serious threat patients' survival. Nevertheless, novel class have not been approved since 1980s. The development antibiotic potentiators is an appealing alternative challenging process searching for new antimicrobials. Production H2S-one leading defense mechanisms crucial survival-can be influenced by inhibition relevant enzymes: cystathionine γ-lyase (bCSE), β-synthase (bCBS), or 3-mercaptopyruvate sulfurtransferase (MST). first one makes main contribution H2S generation. Herein, we present data on synthesis, in silico analyses, and enzymatic microbiological assays bCSE inhibitors. Combined molecular docking dynamics analyses revealed binding mode these ligands bCSE. Lead compound 2a manifested strong potentiating activity when applied combination with some commonly used against multidrug-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus. was found favorable vitro absorption, distribution, metabolism, excretion, toxicity parameters. high effectiveness safety it promising candidate enhancing high-priority pathogens.

Язык: Английский

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Exploring the Antiviral Potential of Esters of Cinnamic Acids with Quercetin

Viruses, Год журнала: 2024, Номер 16(5), С. 665 - 665

Опубликована: Апрель 24, 2024

Severe acute respiratory syndrome-related Coronavirus 2 (SARS-CoV-2) has infected more than 762 million people to date and caused approximately 7 deaths all around the world, involving 187 countries. Although currently available vaccines show high efficacy in preventing severe complications patients, number of mutations S proteins current variants is responsible for level immune evasion transmissibility virus reduced effectiveness acquired immunity. In this scenario, development safe effective drugs synthetic or natural origin suppress viral replication treat forms COVID-19 remains a valid therapeutic challenge. Given successful history flavonoids-based drug discovery, we developed esters substituted cinnamic acids with quercetin evaluate their vitro activity against broad spectrum Coronaviruses. Interestingly, two derivatives, 3,4-methylenedioxy 6 ester acid 7, have proved be reducing OC43-induced cytopathogenicity, showing interesting EC50s profiles. The synaptic particular, which not endowed relevant cytotoxicity under any tested conditions, turned out active OC43 SARS-CoV-2, promising EC50. Therefore, said compound was selected as lead object further analysis. When yield reduction, assay produced significant dose-dependent reduction titer. However, virucidal, exposure concentrations it did affect infectivity, nor hCoV-OC43 penetration into pre-treated host cells. Additional studies on action mechanism suggested that our derivative may inhibit endocytosis by attachment

Язык: Английский

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Synthesis, Antimicrobial and Antibiofilm Activities, and Molecular Docking Investigations of 2-(1H-Indol-3-yl)-1H-benzo[d]imidazole Derivatives

Molecules, Год журнала: 2023, Номер 28(20), С. 7095 - 7095

Опубликована: Окт. 14, 2023

The treatment of many bacterial and fungal infections remains a problem due to increasing antibiotic resistance biofilm formation by pathogens. In the present article, methodology for chemoselective synthesis 2-(1H-indol-3-yl)-1H-benzo[d]imidazole derivatives is presented. We report on antimicrobial activity synthesized 2-(1H-indol-3-yl)-1H-benzo[d]imidazoles with significant against Staphylococcus aureus ATCC 25923, 43300 (MRSA), Mycobacterium smegmatis (mc(2)155/ATCC 700084), Candida albicans 10231. High staphylococci was shown indolylbenzo[d]imidazoles 3ao 3aq (minimum inhibitory concentration (MIC) < 1 µg/mL) 3aa 3ad (MIC 3.9-7.8 µg/mL). A low MIC demonstrated 2-(1H-indol-3-yl)-1-methyl-1H-benzo[d]imidazole (3ag) M. C. (3.9 µg/mL 3.9 µg/mL, respectively). 2-(5-Bromo-1H-indol-3-yl)-6,7-dimethyl-1H-benzo[d]imidazole (3aq) showed albicans. Compounds 3aa, 3ad, 3ao, exhibited excellent antibiofilm activity, inhibiting killing cells in mature biofilms. Molecular docking analysis identified three potential interaction models investigated compounds, implicating (p)ppGpp synthetases/hydrolases, FtsZ proteins, or pyruvate kinases their antibacterial action mechanism.

Язык: Английский

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5‐Arylidene‐2,4‐thiazolidinediones as Cysteine Protease Inhibitors against Leishmania Donovani

ChemistrySelect, Год журнала: 2023, Номер 8(29)

Опубликована: Авг. 2, 2023

Abstract A series of 5‐arylidene‐2,4‐thiazolidinediones were synthesized using Knoevenagel condensation and evaluated for their anti‐leishmanial activity against L. donovani promastigotes axenic amastigotes. Among the compounds tested, three most active, with IC 50 values 0.82–1.42 μM 0.69–1.19 amastigote. ( Z )‐5‐(4‐(trifluoromethyl)benzylidene)thiazolidine‐2,4‐dione was prominent among all tested demonstrated better properties when compared to standard drug miltefosine (1.26 1.17 amastigotes). It insignificantly toxic in THP‐1 human monocytic cells. further its vitro cysteine protease (papain) inhibitory Z‐RR‐AMC fluorogenic peptide substrate. promising value 3.42 μM. In silico docking studies also supported that is bound proteins′ catalytic active binding site. Anti‐leishmanial this class have been first time, emerged as a lead molecule from library tested. This may serve template discovery Leishmania.

Язык: Английский

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Synthesis of α-fluorocinnamate derivatives as novel cathepsin S inhibitors with in vitro antiproliferative activity against pancreatic cancer cells

Bioorganic & Medicinal Chemistry, Год журнала: 2024, Номер 115, С. 117987 - 117987

Опубликована: Ноя. 5, 2024

Язык: Английский

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Machine-Learning- and Structure-Based Virtual Screening for Selecting Cinnamic Acid Derivatives as Leishmania major DHFR-TS Inhibitors

Molecules, Год журнала: 2023, Номер 29(1), С. 179 - 179

Опубликована: Дек. 28, 2023

The critical enzyme dihydrofolate reductase-thymidylate synthase in Leishmania major (LmDHFR-TS) serves a dual-purpose role and is essential for DNA synthesis, cornerstone of the parasite’s reproductive processes. Consequently, development inhibitors against LmDHFR-TS crucial creation novel anti-Leishmania chemotherapies. In this study, we employed an in-house database containing 314 secondary metabolites derived from cinnamic acid that occurred Asteraceae family. We conducted combined ligand/structure-based virtual screening to identify potential LmDHFR-TS. Through consensus analysis both approaches, identified three compounds, i.e., lithospermic (237), diarctigenin (306), isolappaol A (308), exhibited high probability being according approaches were consequently classified as promising hits. Subsequently, expanded binding mode examination these compounds within active site test through molecular dynamics simulations, revealing degree structural stability minimal fluctuations its tertiary structure. silico predictions then validated vitro assays examine inhibitory capacity top-ranked naturally occurring recombinant protein. effectively inhibited with IC50 values ranging 6.1 10.1 μM. contrast, other common derivatives (i.e., flavonoid glycosides) family, such hesperidin, isovitexin 4′-O-glucoside, rutin, low activity target. selective index (SI) all tested was determined using HsDHFR moderate effect. Among hits, lignans 306 308 demonstrated highest selectivity, displaying superior SI compared methotrexate, reference inhibitor DHFR-TS. Therefore, continued research into anti-leishmanial C6C3-hybrid butyrolactone may offer brighter outlook combating neglected tropical disease.

Язык: Английский

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