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1.
Acta Crystallogr E Crystallogr Commun ; 80(Pt 10): 1034-1038, 2024 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-39372169

RESUMEN

The crystal structure of the title compound C20H17NO2S features hydrogen-bonding and C-H⋯π inter-actions. Hirshfeld surface analysis revealed that H⋯H, C⋯H/H⋯C and O⋯H/H⋯O inter-actions make a major contribution to the crystal packing. Docking studies were carried out to determine the binding affinity and inter-action profile of the title compound with EGFR kinase, a member of the ErbB family of receptor tyrosine kinases, which is crucial for processes such as cell proliferation and differentiation. The title compound shows a strong binding affinity with EGFR kinase, with the most favourable conformation having a binding energy of -8.27 kcal mol-1 and a predicted IC50 of 870.34 nM, indicating its potential as a promising candidate for targeted lung cancer therapy.

2.
Bioorg Med Chem ; 114: 117958, 2024 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-39427529

RESUMEN

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.

3.
Bioorg Chem ; 153: 107881, 2024 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-39396453

RESUMEN

As inhibitors of carbonic anhydrases (CAs) IX and XII, a novel series of 1,2,3-triazole benzenesulfonamide derivatives 17a-l containing pyrazolyl-thiazole moiety was designed, synthesized, and tested for anti-proliferative activity. Compounds 17e-h demonstrated more effective inhibitory activity than acetazolamide (IC50 63 nM CA IX and IC50 92 nM CA XII), with IC50 range of 25-52 nM against CA IX and IC50 range of 31-80 nM against CA XII. To verify selectivity against CA IX and CA XII, carbonic anhydrase inhibitory activity of compounds 17e-h against the physiological CA I and CA II isoforms was carried out. The results showed that compounds 17e-h induced lower inhibitory activity against CA I and CA II with IC50 range of 0.428-0.638 µM (CA I) and 0.095-0.164 µM (CA II), in addition to higher selectivity indices (CA I/CA IX S.I. 8.9-19.92, CA I/CA XII S.I. 5.78-16.06) and (CA II/CA IX S.I. 2.83-4.35, CA II/CA XII S.I. 2.05-3.15) when compared to that of acetazolamide, IC50 of 0.199 µM (CA I), 0.133 µM (CA II) (CA I/CA IX S.I. 3.15, CA I/CA XII S.I. 2.16) and (CA II/CA IX S.I. 2.11, CA II/CA XII S.I. 1.44). Concerning anti-proliferative activity of compounds 17e-h, investigations were done on HEPG-2 cell line with IC50 ranges of 3.44-15.03 µM in comparison, 5-FU and doxorubicin showed IC50 values of 11.80 and 9.53 µM, respectively. Furthermore IC50 of MCF-7 and MDA-MB-231 were determined under both normoxic and hypoxic conditions with IC50 values ranging from 3.18-8.26 µM MCF-7 (normoxic), 1.39-6.05 µM MCF-7 (hypoxic), 7.13-26.3 µM MDA-MB-231 (normoxic), 0.76-16.3 µM MDA-MB-231 (hypoxic) using acetazolamide and SLC-0111 as selective CA inhibition references. Moreover, compounds 17e-h demonstrated greater safety against the normal cell line, MCF-10A, with IC50 of 23.06-99.50 µM in comparison to 5-FU and doxorubicin IC50 of 59.8 and 71.8 µM respectively. They also demonstrated (MCF-7 S.I. range of 3.77-31.28) in contrast to doxorubicin (S.I. 13.72) and (HepG-2 S.I. range of 3.60-6.95) in comparison to doxorubicin (S.I. 7.53). In relation to CA IX, XII inhibition, molecular docking of and ADME studies of sulfonamide derivatives 17a-l with CA IX (PDB: 5FL6) and CA XII (PDB: 1JD0) was carried out. Additionally, molecular dynamic simulation was carried out for compounds 17e and 17g which maintained good stability inside the active sites of both enzymes, with average RMSDs of 2.3 Å and 2.1 Å, respectively.

4.
Molecules ; 29(18)2024 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-39339439

RESUMEN

Human Carbonic Anhydrases (hCA) are enzymes that contribute to cancer's development and progression. Isoforms IX and XII have been identified as potential anticancer targets, and, more specifically, hCA IX is overexpressed in hypoxic tumor cells, where it plays an important role in reprogramming the metabolism. With the aim to find new inhibitors towards IX and XII isoforms, the hybridization of the privileged scaffolds isatin, dihydrothiazole, and benzenesulfonamide was investigated in order to explore how it may affect the activity and selectivity of the hCA isoforms. In this respect, a series of isatin thiazolidinone hybrids have been designed and synthesized and their biological activity and selectivity on hCA I, hCA II, hCA IX, and hCA XII explored. The new compounds exhibited promising inhibitory activity results on isoforms IX and XII in the nanomolar range, which has highlighted the importance of substituents in the isatin ring and in position 3 and 5 of thiazolidinone. In particular, compound 5g was the most active toward hCA IX, while 5f was the most potent inhibitor of hCA XII within the series. When both potency and selectivity were considered, compound 5f appeared as one of the most promising. Additionally, our investigations were supported by molecular docking experiments, which have highlighted the putative binding poses of the most promising compound.


Asunto(s)
Inhibidores de Anhidrasa Carbónica , Anhidrasas Carbónicas , Diseño de Fármacos , Simulación del Acoplamiento Molecular , Inhibidores de Anhidrasa Carbónica/química , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/síntesis química , Humanos , Anhidrasas Carbónicas/química , Anhidrasas Carbónicas/metabolismo , Relación Estructura-Actividad , Anhidrasa Carbónica IX/antagonistas & inhibidores , Anhidrasa Carbónica IX/metabolismo , Anhidrasa Carbónica IX/química , Estructura Molecular , Isatina/química , Isatina/farmacología , Isatina/análogos & derivados
5.
Chemistry ; 30(58): e202402330, 2024 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-39109590

RESUMEN

Amyloid-beta aggregation is considered one of the factors influencing the onset of the Alzheimer's disease. Early prevention of such aggregation should alleviate disease condition by applying small molecule compounds that shift the aggregation equilibrium toward the soluble form of the peptide or slow down the process. We have discovered that fluorinated benzenesulfonamides of particular structure slowed the amyloid-beta peptide aggregation process by more than three-fold. We synthesized a series of ortho-para and meta-para double-substituted fluorinated benzenesulfonamides that inhibited the aggregation process to a variable extent yielding a detailed picture of the structure-activity relationship. Analysis of compound chemical structure effect on aggregation in artificial cerebrospinal fluid showed the necessity to arrange the benzenesulfonamide, hydrophobic substituent, and benzoic acid in a particular way. The amyloid beta peptide aggregate fibril structures varied in cross-sectional height depending on the applied inhibitor indicating the formation of a complex with the compound. Application of selected inhibitors increased the survivability of cells affected by the amyloid beta peptide. Such compounds may be developed as drugs against Alzheimer's disease.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Bencenosulfonamidas , Sulfonamidas , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/química , Sulfonamidas/química , Sulfonamidas/farmacología , Relación Estructura-Actividad , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Agregado de Proteínas/efectos de los fármacos , Halogenación , Interacciones Hidrofóbicas e Hidrofílicas , Animales
6.
Arch Pharm (Weinheim) ; 357(10): e2400114, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38900588

RESUMEN

The design and synthesis of a library of 21 novel benzenesulfonamide-bearing 3-functionalized pyrazole-linked 1,2,3-triazole derivatives as dual inhibitors of cathepsin B and carbonic anhydrase enzymes are reported. The target 1,2,3-triazole-linked pyrazolic esters (16) were synthesized by the condensation of 1,2,3-triazolic diketo esters with 4-hydrazinobenzenesulfonamide hydrochloride, and these were further converted into the corresponding carboxylic acid (17) and carboxamide (18) analogs. The synthesized compounds were assayed in vitro for their inhibition potential against human carbonic anhydrase (hCA) isoforms I, II, IX, and XII. They were found to be potent inhibitors at the low nanomolar level against the cancer-related hCA IX and XII and to be selective towards the cytosolic isoform hCA I. The physiologically important isoform hCA II was potently inhibited by all the newly synthesized compounds showing KI values ranging between 0.8 and 561.5 nM. The ester derivative 16c having 4-fluorophenyl (KI = 5.2 nM) was the most potent inhibitor of hCA IX, and carboxamide derivative 18b (KI = 2.2 nM) having 4-methyl substituted phenyl was the most potent inhibitor of hCA XII. The newly synthesized compounds exhibited potent cathepsin B inhibition at 10-7 M concentration. In general, the carboxamide derivatives (18) showed higher % inhibition as compared with the corresponding ester derivatives (16) and carboxylic acid derivatives (17) for cathepsin B. The interactions of the target compounds with the active sites of cathepsin B and CA were studied through molecular docking studies. Further, the in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) and drug-likeness properties of the target compounds were also studied.


Asunto(s)
Bencenosulfonamidas , Inhibidores de Anhidrasa Carbónica , Catepsina B , Pirazoles , Sulfonamidas , Triazoles , Humanos , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Anhidrasas Carbónicas/metabolismo , Catepsina B/antagonistas & inhibidores , Catepsina B/metabolismo , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Pirazoles/farmacología , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-Actividad , Sulfonamidas/farmacología , Sulfonamidas/química , Sulfonamidas/síntesis química , Triazoles/farmacología , Triazoles/química , Triazoles/síntesis química
7.
Bioorg Chem ; 150: 107596, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38941699

RESUMEN

A novel series of 1,8-naphthalimide piperazinamide based benzenesulfonamides derivatives were designed and synthesized as carbonic anhydrase IX (CA IX) inhibitors and ferroptosis inducers for the treatment of triple-negative breast cancer (TNBC). The representative compound 9o exhibited more potent inhibitory activity and selective against CA IX over off-target CA II, compared with positive control SLC-0111. Molecular docking study was also performed to gain insights into the binding interactions of 9o in the binding pocket of CAIX. Moreover, compound 9o exhibited superior antitumor activities against breast cancer cells under hypoxia than that of normoxia conditions. Mechanism studies revealed that compound 9o could act as DNA intercalator and effectively suppressed cell migration, arrested the cell cycle at G1/S phase and induced apoptosis in MDA-MB-231 cells, while inducing ferroptosis accompanied by the dissipation of MMP and the elevation intracellular levels of ROS. Notably, in vivo studies demonstrated that 9o effectively inhibited tumor growth and metastasis in a highly metastatic murine breast cancer 4 T1 xenograft model. Taken together, this study suggests that compound 9o represents a potent and selective CA IX inhibitor and ferroptosis inducer for the treatment of TNBC.


Asunto(s)
Antineoplásicos , Bencenosulfonamidas , Anhidrasa Carbónica IX , Inhibidores de Anhidrasa Carbónica , Proliferación Celular , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Ferroptosis , Naftalimidas , Sulfonamidas , Neoplasias de la Mama Triple Negativas , Humanos , Anhidrasa Carbónica IX/antagonistas & inhibidores , Anhidrasa Carbónica IX/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/química , Inhibidores de Anhidrasa Carbónica/síntesis química , Ferroptosis/efectos de los fármacos , Sulfonamidas/farmacología , Sulfonamidas/química , Sulfonamidas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Animales , Estructura Molecular , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Ratones , Femenino , Naftalimidas/química , Naftalimidas/farmacología , Naftalimidas/síntesis química , Descubrimiento de Drogas , Apoptosis/efectos de los fármacos , Simulación del Acoplamiento Molecular , Piperazinas/farmacología , Piperazinas/química , Piperazinas/síntesis química , Línea Celular Tumoral , Antígenos de Neoplasias
8.
J Agric Food Chem ; 72(20): 11369-11380, 2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38727083

RESUMEN

In keeping with our investigation, a simple and practical synthesis of novel heterocyclic compounds with a sulfamoyl moiety that can be employed as insecticidal agents was reported. The compound 2-hydrazinyl-N-(4-sulfamoylphenyl)-2-thioxoacetamide 1 was coupled smoothly with triethylorthoformate or a variety of halo compounds, namely phenacyl chloride, chloroacetyl chloride, chloroacetaldehyde, chloroacetone, 1,3-dichloropropane, 1,2-dichloroethane, ethyl chloroformate, 2,3-dichloro-1,4-naphthoquinone, and chloroanil respectively, which afforded the 1,3,4-thiadiazole and 1,3,4-thiadiazine derivatives. The new products structure was determined using elemental and spectral analysis. Under laboratory conditions, the biological and toxicological effects of the synthetic compounds were also evaluated as insecticides against Spodoptera littoralis (Boisd.). Compounds 3 and 5 had LC50 values of 6.42 and 6.90 mg/L, respectively. The investigated compounds (from 2 to 11) had been undergoing molecular docking investigation for prediction of the optimal arrangement and strength of binding between the ligand (herein, the investigated compounds (from 2 to 11)) and a receptor (herein, the 2CH5) molecule. The binding affinity within docking score (S, kcal/mol) ranged between -8.23 (for compound 5), -8.12 (for compound 3) and -8.03 (for compound 9) to -6.01 (for compound 8). These compounds were shown to have a variety of binding interactions within the 2CH5 active site, as evidenced by protein-ligand docking configurations. This study gives evidence that those compounds have 2CH5-inhibitory capabilities and hence may be used for 2CH5-targeting development. Furthermore, the three top-ranked compounds (5, 3, and 9) and the standard buprofezin were subjected to density functional theory (DFT) analysis. The highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energy difference (ΔE) of compounds 5, 3, and 9 was found to be comparable to that of buprofezin. These findings highlighted the potential and relevance of charge transfer at the molecular level.


Asunto(s)
Diseño de Fármacos , Insecticidas , Simulación del Acoplamiento Molecular , Spodoptera , Tiadiazinas , Tiadiazoles , Animales , Insecticidas/química , Insecticidas/síntesis química , Insecticidas/farmacología , Spodoptera/efectos de los fármacos , Tiadiazoles/química , Tiadiazoles/farmacología , Tiadiazoles/síntesis química , Tiadiazinas/química , Tiadiazinas/farmacología , Tiadiazinas/síntesis química , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , Sulfonamidas/síntesis química , Proteínas de Insectos/química , Bencenosulfonamidas , Estructura Molecular , Anhidrasa Carbónica II/antagonistas & inhibidores , Anhidrasa Carbónica II/metabolismo , Anhidrasa Carbónica II/química
9.
Arch Pharm (Weinheim) ; 357(8): e2400157, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38713910

RESUMEN

Two novel series of hydrazinyl-based benzenesulfonamides 9a-j and 10a-j were designed and synthesized using SLC-0111 as the lead molecule. The newly synthesized compounds were evaluated for their inhibitory activity against four different human carbonic anhydrase (hCA) isoforms I, II, IX, and XII. Both the series reported here were practically inactive against the off-target isozyme hCA I. Notably, derivative 10a exhibited superior potency (Ki of 10.2 nM) than acetazolamide (AAZ) against the cytosolic isoform hCA II. The hCA IX and XII isoforms implicated in tumor progression were effectively inhibited with Kis in the low nanomolar range of 20.5-176.6 nM and 6.0-127.5 nM, respectively. Compound 9g emerged as the most potent and selective hCA IX and XII inhibitor with Ki of 20.5 nM and SI of 200.1, and Ki of 6.0 nM and SI of 683.7, respectively, over hCA I. Furthermore, six compounds (9a, 9h, 10a, 10g, 10i, and 10j) exhibited significant inhibition toward hCA IX (Kis = 27.0, 41.1, 27.4, 25.9, 40.7, and 30.8 nM) relative to AAZ and SLC-0111 (Kis = 25.0 and 45.0 nM, respectively). These findings underscore the potential of these derivatives as potent and selective inhibitors of hCA IX and XII over the off-target hCA I and II.


Asunto(s)
Inhibidores de Anhidrasa Carbónica , Anhidrasas Carbónicas , Sulfonamidas , Humanos , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Relación Estructura-Actividad , Anhidrasas Carbónicas/metabolismo , Sulfonamidas/farmacología , Sulfonamidas/química , Sulfonamidas/síntesis química , Estructura Molecular , Diseño de Fármacos , Antígenos de Neoplasias/metabolismo , Isoenzimas/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Anhidrasa Carbónica IX/antagonistas & inhibidores , Anhidrasa Carbónica IX/metabolismo , Anhidrasa Carbónica II/antagonistas & inhibidores , Anhidrasa Carbónica II/metabolismo , Simulación por Computador , Simulación del Acoplamiento Molecular , Compuestos de Fenilurea
10.
J Exp Clin Cancer Res ; 43(1): 137, 2024 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-38711119

RESUMEN

BACKGROUND: The C-terminal-binding protein 1/brefeldin A ADP-ribosylation substrate (CtBP1/BARS) acts both as an oncogenic transcriptional co-repressor and as a fission inducing protein required for membrane trafficking and Golgi complex partitioning during mitosis, hence for mitotic entry. CtBP1/BARS overexpression, in multiple cancers, has pro-tumorigenic functions regulating gene networks associated with "cancer hallmarks" and malignant behavior including: increased cell survival, proliferation, migration/invasion, epithelial-mesenchymal transition (EMT). Structurally, CtBP1/BARS belongs to the hydroxyacid-dehydrogenase family and possesses a NAD(H)-binding Rossmann fold, which, depending on ligands bound, controls the oligomerization of CtBP1/BARS and, in turn, its cellular functions. Here, we proposed to target the CtBP1/BARS Rossmann fold with small molecules as selective inhibitors of mitotic entry and pro-tumoral transcriptional activities. METHODS: Structured-based screening of drug databases at different development stages was applied to discover novel ligands targeting the Rossmann fold. Among these identified ligands, N-(3,4-dichlorophenyl)-4-{[(4-nitrophenyl)carbamoyl]amino}benzenesulfonamide, called Comp.11, was selected for further analysis. Fluorescence spectroscopy, isothermal calorimetry, computational modelling and site-directed mutagenesis were employed to define the binding of Comp.11 to the Rossmann fold. Effects of Comp.11 on the oligomerization state, protein partners binding and pro-tumoral activities were evaluated by size-exclusion chromatography, pull-down, membrane transport and mitotic entry assays, Flow cytometry, quantitative real-time PCR, motility/invasion, and colony assays in A375MM and B16F10 melanoma cell lines. Effects of Comp.11 on tumor growth in vivo were analyzed in mouse tumor model. RESULTS: We identify Comp.11 as a new, potent and selective inhibitor of CtBP1/BARS (but not CtBP2). Comp.11 directly binds to the CtBP1/BARS Rossmann fold affecting the oligomerization state of the protein (unlike other known CtBPs inhibitors), which, in turn, hinders interactions with relevant partners, resulting in the inhibition of both CtBP1/BARS cellular functions: i) membrane fission, with block of mitotic entry and cellular secretion; and ii) transcriptional pro-tumoral effects with significantly hampered proliferation, EMT, migration/invasion, and colony-forming capabilities. The combination of these effects impairs melanoma tumor growth in mouse models.  CONCLUSIONS: This study identifies a potent and selective inhibitor of CtBP1/BARS active in cellular and melanoma animal models revealing new opportunities to study the role of CtBP1/BARS in tumor biology and to develop novel melanoma treatments.


Asunto(s)
Oxidorreductasas de Alcohol , Proteínas de Unión al ADN , Melanoma , Humanos , Oxidorreductasas de Alcohol/antagonistas & inhibidores , Oxidorreductasas de Alcohol/metabolismo , Oxidorreductasas de Alcohol/genética , Animales , Ratones , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/metabolismo , Melanoma/genética , Línea Celular Tumoral , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/genética , Proliferación Celular/efectos de los fármacos , Antineoplásicos/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Future Med Chem ; 16(8): 689-706, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38573017

RESUMEN

Background: Exploration of the multi-target approach considering both human carbonic anhydrase (hCA) IX and XII and cathepsin B is a promising strategy to target cancer. Methodology & Results: 22 novel 1,2,4-triazole derivatives were synthesized and evaluated for their inhibition efficacy against hCA I, II, IX, XII isoforms and cathepsin B. The compounds demonstrated effective inhibition against hCA IX and/or XII isoforms with considerable selectivity over off-target hCA I/II. All compounds presented significant anticathepsin B activities at a low concentration of 10-7 M and in vitro results were also supported by the molecular modeling studies. Conclusion: Insights of present study can be utilized in the rational design of effective and selective hCA IX and XII inhibitors capable of inhibiting cathepsin B.


[Box: see text].


Asunto(s)
Inhibidores de Anhidrasa Carbónica , Catepsina B , Triazoles , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/química , Inhibidores de Anhidrasa Carbónica/síntesis química , Humanos , Triazoles/química , Triazoles/farmacología , Triazoles/síntesis química , Catepsina B/antagonistas & inhibidores , Catepsina B/metabolismo , Relación Estructura-Actividad , Anhidrasas Carbónicas/metabolismo , Estructura Molecular , Simulación del Acoplamiento Molecular , Modelos Moleculares
12.
Eur J Med Chem ; 271: 116434, 2024 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-38653067

RESUMEN

Diabetes mellitus is a chronic metabolic disorder characterized by improper expression/function of a number of key enzymes that can be regarded as targets for anti-diabetic drug design. Herein, we report the design, synthesis, and biological assessment of two series of thiazolidinone-based sulfonamides 4a-l and 5a-c as multitarget directed ligands (MTDLs) with potential anti-diabetic activity through targeting the enzymes: α-glucosidase and human carbonic anhydrase (hCA) II. The synthesized sulfonamides were evaluated for their inhibitory activity against α-glucosidase where most of the compounds showed good to potent activities. Compounds 4d and 4e showed potent inhibitory activities (IC50 = 0.440 and 0.3456 µM), comparable with that of the positive control (acarbose; IC50 = 0.420 µM). All the synthesized derivatives were also tested for their inhibitory activities against hCA I, II, IX, and XII. They exhibited different levels of inhibition against these isoforms. Compound 4d outstood as the most potent one against hCA II with Ki equals to 7.0 nM, more potent than the reference standard (acetazolamide; Ki = 12.0 nM). In silico studies for the most active compounds within the active sites of α-glucosidase and hCA II revealed good binding modes that can explain their biological activities. MM-GBSA refinements and molecular dynamic simulations were performed on the top-ranking docking pose of the most potent compound 4d to confirm the formation of stable complex with both targets. Compound 4d was screened for its in vivo antihyperglycemic efficacy by using the oral glucose tolerance test. Compound 4d decreased blood glucose level to 217 mg/dl, better than the standard acarbose (234 mg/dl). Hence, this revealed its synergistic mode of action on post prandial hyperglycemia and hepatic gluconeogenesis. Thus, these benzenesulfonamide thiazolidinone hybrids could be considered as promising multi-target candidates for the treatment of type II diabetes mellitus.


Asunto(s)
Bencenosulfonamidas , Anhidrasa Carbónica II , Inhibidores de Anhidrasa Carbónica , Diabetes Mellitus Tipo 2 , Inhibidores de Glicósido Hidrolasas , Hipoglucemiantes , Sulfonamidas , Tiazolidinas , alfa-Glucosidasas , Anhidrasa Carbónica II/antagonistas & inhibidores , Anhidrasa Carbónica II/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , alfa-Glucosidasas/metabolismo , Humanos , Sulfonamidas/química , Sulfonamidas/farmacología , Sulfonamidas/síntesis química , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/química , Inhibidores de Glicósido Hidrolasas/síntesis química , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Hipoglucemiantes/síntesis química , Relación Estructura-Actividad , Inhibidores de Anhidrasa Carbónica/química , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/síntesis química , Animales , Ligandos , Tiazolidinas/química , Tiazolidinas/farmacología , Tiazolidinas/síntesis química , Estructura Molecular , Ratas , Relación Dosis-Respuesta a Droga , Simulación del Acoplamiento Molecular , Diabetes Mellitus Experimental/tratamiento farmacológico , Masculino , Ratas Wistar
13.
Anticancer Agents Med Chem ; 24(9): 649-667, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38367264

RESUMEN

INTRODUCTION: Carbonic anhydrases (CAs) are widespread metalloenzymes with the core function of catalyzing the interconversion of CO2 and HCO3 -. Targeting these enzymes using selective inhibitors has emerged as a promising approach for the development of novel therapeutic agents against multiple diseases. METHODS: A series of novel thiosemicarbazone-containing derivatives were synthesized, characterized, and tested for their inhibitory activity against pharmaceutically important human CA I (hCA I), II (hCA II), IX (hCA IX), and XII (hCA XII) using the single tail approach. RESULTS: The compounds generally inhibited the isoenzymes at low nanomolar concentrations, with compound 6b having Ki values of 7.16, 0.31, 92.5, and 375 nM against hCA I, II, IX and XII, respectively. Compound 6e exhibited Ki values of 27.6, 0.34, 872, and 94.5 nM against hCA I, II, IX and XII, respectively. CONCLUSION: To rationalize the inhibition data, molecular docking studies were conducted, providing insight into the binding mechanisms, molecular interactions, and selectivity of the compounds towards the isoenzymes.


Asunto(s)
Bencenosulfonamidas , Inhibidores de Anhidrasa Carbónica , Anhidrasas Carbónicas , Sulfonamidas , Tiosemicarbazonas , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Humanos , Sulfonamidas/química , Sulfonamidas/farmacología , Sulfonamidas/síntesis química , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/síntesis química , Anhidrasas Carbónicas/metabolismo , Relación Estructura-Actividad , Estructura Molecular , Simulación del Acoplamiento Molecular , Relación Dosis-Respuesta a Droga
14.
Acta Crystallogr E Crystallogr Commun ; 80(Pt 2): 120-124, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38333139

RESUMEN

The title compound, C10H11N5O2S2, consists of an unexpected tautomer with a protonated nitro-gen atom in the triazine ring and a formal exocyclic double bond C=N to the sulfonamide moiety. The ring angles at the unsubstituted nitro-gen atoms are narrow, at 115.57 (12) and 115.19 (12)°, respectively, whereas the angle at the carbon atom between these N atoms is very wide, 127.97 (13)°. The inter-planar angle between the two rings is 79.56 (5)°. The mol-ecules are linked by three classical hydrogen bonds, forming a ribbon structure. There are also unusual linkages involving three short contacts (< 3 Å) from a sulfonamide oxygen atom to the C-NH-C part of a triazine ring.

15.
J Biomol Struct Dyn ; 42(7): 3441-3458, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37232497

RESUMEN

The synthesis and biological assessment of novel multi-functionalized pyrrolidine-containing benzenesulfonamides were reported along with their antimicrobial, antifungal, CAs inhibition, and AChE inhibition as well as DNA-binding effects. The chemical structure of the compounds was elucidated by using FTIR, NMR, and HRMS. Compound 3b, which had Ki values of 17.61 ± 3.58 nM (hCA I) and 5.14 ± 0.61 nM (hCA II), was found the be the most potent CAs inhibitor. Compounds 6a and 6b showed remarkable AChE inhibition effects with Ki values 22.34 ± 4.53 nM and 27.21 ± 3.96 nM in comparison to tacrine. Compounds 6a-6c had moderate antituberculosis effect on M. tuberculosis with a MIC value of 15.62 µg/ml. Compounds had weaker antifungal and antibacterial activity in the range of MIC 500-62.5 µg/ml against standard bacterial and fungal strains. Besides these above, molecular docking studies were performed to examine and evaluate the interaction of the remarkable compounds (3b, 6a and 6b) against the current enzymes (CAs and AChE). Novel compounds gained interest in terms of enzyme inhibitory potencies. Therefore, the most potent enzyme inhibitors may be considered lead compounds to be modified for further research.Communicated by Ramaswamy H. Sarma.


Asunto(s)
Antiinfecciosos , Anhidrasas Carbónicas , Inhibidores de la Colinesterasa/química , Bencenosulfonamidas , Acetilcolinesterasa/química , Antifúngicos/farmacología , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/química , Simulación del Acoplamiento Molecular , Anhidrasa Carbónica I/metabolismo , Anhidrasa Carbónica II/metabolismo , Antiinfecciosos/farmacología , Relación Estructura-Actividad , Estructura Molecular
16.
Arch Pharm (Weinheim) ; 357(3): e2300650, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38154111

RESUMEN

A library of 20 novel benzenesulfonamide incorporating thiazole tethered 1,2,3-triazoles 1-4a-e was synthesized and screened for their antimicrobial, antioxidant, and cytotoxicity studies. Amoxicillin and fluconazole were used as reference antibacterial and antifungal drugs, respectively. Further, energies of frontier molecular orbitals were calculated for all the synthesized target compounds 1-4a-e to correlate electronic parameters with the observed biological results. Global reactivity descriptors, including highest occupied molecular orbitals-lowest unoccupied molecular orbitals energy gap, electronegativity, chemical hardness, chemical softness, and electrophilicity index, were also calculated for the synthesized molecules. All the tested compounds possessed moderate to excellent antibacterial potency; however, 3d and 4d exhibited the overall highest antibacterial effect (minimum inhibitory concentration [MIC] values 5-11 µM) while 2c showed the highest antifungal effect (MIC value 6 µM). Compound 3c exhibited the highest antioxidant activity with a % radical scavenging activity value of 95.12. The cytotoxicity of the compounds 1-4a-e was also checked against an animal cell line and a plant seed germination cell line, and the compounds were found to be safe against both the tested cell lines.


Asunto(s)
Antiinfecciosos , Antifúngicos , Animales , Antifúngicos/farmacología , Triazoles/farmacología , Antioxidantes/farmacología , Bencenosulfonamidas , Relación Estructura-Actividad , Antibacterianos/farmacología , Pruebas de Sensibilidad Microbiana , Tiazoles/farmacología , Estructura Molecular
17.
Heliyon ; 9(11): e21518, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-38027984

RESUMEN

We present in this paper a direct and efficient study regarding synthesis and spectral characterization of three series of hybrid quinoline anchored with 4-R-benzenesulfonamide moiety, with potential antimicrobial activity, by using ultrasound (US) irradiation and conventional methods (CV). The synthesis pathway is efficient and direct, in two steps: an initial N-acylation of 8-aminoquinoline followed by metal complexation with variously M2+ metals (Cd2+, Co2+, Cu2+, Ni2+, Pd2+, Zn2+). For both type of reactions, N-acylation and complexation, under US irradiations the synthesis have some undeniable advantages: the most relevant being the higher yields, a dramatically decrease for reaction time (with about 150 (one hundred fifty) folds for complexation) comparative with conventional methods (CV) (therefore the spent energy decrease in the same way), a decrease of the amount of used solvents. Taking into account the above considerations these reactions setup could be appreciated as eco-friendly. The structures of the obtained hybrid quinoline - sulfonamide complexes (HQBSM) were determined by elemental analysis and by using spectral investigations: FT-IR, NMR experiments, and X-ray diffraction (in three cases). The FT-IR and NMR spectra of complexes show a similar spectroscopic pattern for all complexes and fully confirm the proposed structures. The X-ray spectra analyses prove without doubts the structure of metal complexes, indicating that their structure depends essentially by two factors: the nature of metal and the nature of sulfonamide-quinoline moieties. Complexes containing 4-methoxy-benzoyl moiety and Zn2+ (e.g. 6a) are tetra-coordinated while in the Ni2+ complex (e.g. 6e) the metallic ion forms a distorted square-based bi-pyramid. In the complexes containing 4-nitro-benzoyl moiety and Cd2+ (e.g. 5d) the metallic ion forms a triangular bipyramid. The antibacterial and antifungal assay reveal that only hybrid HQBSM complex (4e) (with 4-chlorophenyl moiety and Ni2+ in molecule) have a significant antibacterial activity.

18.
Future Med Chem ; 15(20): 1865-1883, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37886837

RESUMEN

Aim: Development of dual-acting antibacterial agents containing Erlotinib, a recognized EGFR inhibitor used as an anticancer agent, with differently spaced benzenesulfonamide moieties known to bind and inhibit Helicobacter pylori carbonic anhydrase (HpCA) or the antiviral Zidovudine. Methods & materials: Through rational design, ten derivatives were obtained via a straightforward synthesis including a click chemistry reaction. Inhibitory activity against a panel of pathogenic carbonic anhydrases and antibacterial susceptibility of H. pylori ATCC 43504 were assessed. Docking studies on α-carbonic anhydrase enzymes and EGFR were conducted to gain insight into the binding mode of these compounds. Results & conclusion: Some compounds proved to be strong inhibitors of HpCA and showed good anti-H. pylori activity. Computational studies on the targeted enzymes shed light on the interaction hotspots.


Asunto(s)
Anhidrasas Carbónicas , Helicobacter pylori , Anhidrasas Carbónicas/metabolismo , Helicobacter pylori/metabolismo , Clorhidrato de Erlotinib/farmacología , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/química , Receptores ErbB/metabolismo , Relación Estructura-Actividad , Estructura Molecular , Anhidrasa Carbónica IX , Bencenosulfonamidas
19.
Eur J Med Chem ; 261: 115805, 2023 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-37748386

RESUMEN

This study aimed to design potent carbonic anhydrase inhibitors (CAIs) based on pyrazole benzenesulfonamide core. Nine series of substituted pyrazole benzenesulfonamide compounds were synthesized with variable groups like sulphamoyl group as in compounds 4a-e, its bioisosteric carboxylic acid as in compounds 5a-e and 8e, ethyl carboxylate ester as in compounds 6a-e and 9a-e, which were designed as potential prodrugs, isothiazole ring as in compound 7, hydrazide derivative 10e, hydroxamic acid derivatives 11a-e and semicarbazide derivatives 12a-c,e. All the synthesized compounds were investigated for their carbonic anhydrase (CA) inhibitory activity against two human CA isoforms hCA IX and hCA XII and compared to acetazolamide (AAZ). Also, the compounds were assessed for their anticancer activity against 60 cancer cell lines according to the US NCI protocol. Compounds 4b, 5b, 5d, 5e, 6b, 9b, 9e and 11b revealed significant inhibitory activity against both isoforms hCA IX and hCA XII, while 6e, 9d, 11d and 11e showed significant inhibitory activity against hCA XII only compared to acetazolamide as a reference. This would highlight these compounds as promising anticancer drugs. Moreover, compound 6e revealed a remarkable cytostatic activity against CNS cancer cell line (SF-539; TGI = 5.58 µM), renal cancer cell line (786-0; TGI = 4.32 µM) and breast cancer cell line (HS 578 T; TGI = 5.43 µM). Accordingly, compound 6e was subjected to cell cycle analysis and apoptotic assay on the abovementioned cell lines at the specified GI50 (0.45, 0.89 and 1.18 µM, respectively). Also, it revealed the increment of total apoptotic cells percentage in 786-0 (53.19%), SF-539 (46.11%) and HS 578 T (43.55%) relative to the control cells (2.07, 2.64 and 2.52%, respectively). In silico prediction of BBB permeability showed that most of the calculations for compound 6e resulted as BBB (+), which is required for a compound targeting CNS. Further, the interaction of the most active compounds with the key amino acids in the active sites of hCA IX and hCA XII was highlighted by molecular docking analysis.


Asunto(s)
Inhibidores de Anhidrasa Carbónica , Anhidrasas Carbónicas , Humanos , Inhibidores de Anhidrasa Carbónica/química , Anhidrasas Carbónicas/metabolismo , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Acetazolamida/farmacología , Anhidrasa Carbónica IX/metabolismo , Isoformas de Proteínas/metabolismo , Pirazoles/farmacología , Pirazoles/química , Estructura Molecular , Bencenosulfonamidas
20.
J Agric Food Chem ; 71(37): 13645-13653, 2023 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-37676131

RESUMEN

The viral protein genome-linked protein (VPg) of telosma mosaic virus (TeMV) plays an important role in viral reproduction. In this study, the expression conditions of TeMV VPg were explored. A series of novel benzenesulfonamide derivatives were synthesized. The binding sites of the target compounds and TeMV VPg were studied by molecular docking, and the interaction was verified by microscale thermophoresis. The study revealed that the optimal expression conditions for TeMV VPg were in Escherichia coli Rosetta with IPTG concentration of 0.8 mM and induction temperature of 25 °C. Compounds A4, A6, A9, A16, and A17 exhibited excellent binding affinity to TeMV VPg, with Kd values of 0.23, 0.034, 0.19, 0.086, and 0.22 µM, respectively. LYS 121 is the key amino acid site. Compounds A9 inhibited the expression of TeMV VPg in Nicotiana benthamiana. The results suggested that TeMV VPg is a potential antiviral target to screen anti-TeMV compounds.


Asunto(s)
Potyvirus , Proteínas Virales , Proteínas Virales/genética , Simulación del Acoplamiento Molecular , Aminoácidos , Sitios de Unión , Escherichia coli/genética
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