RESUMEN
In the present study, the design and synthesis of novel coumarin derivatives 8a-h, 11a-d and 16a-c as potential selective inhibitors for the tumor associated human carbonic anhydrase isoforms (hCA IX and XII) was reported. All the newly synthesized derivatives showed potent to mild activity against the targeted CA IX (KI = 0.08-9.57 µM), with selectivity indices over CA I (SI = 2.0-21.9) and over CA II (SI = 1.1-15.7). They showed similar activities against CA XII (KI = 0.06-9.48 µM) with selectivity indices over CA I (SI = 1.4-21.2) and CA II (SI = 0.9-15.5). Compound 16b featuring sulfonamide function possessed promising inhibitory activities against the targeted isoforms CA IX and XII with KI values of 0.08 and 0.06 µM, respectively. Interestingly, it was found that using compound 16b at a nontoxic concentration as an adjuvant with Doxorubicin against MCF-7 cells enhanced the cytotoxicity under hypoxia by almost 3.5 folds; IC50 decreased from 25.74 to 7.43 µM. Therefore, compound 16b restored the cytotoxicity of Doxorubicin against MCF-7 cells under hypoxia, almost as normoxia. Furthermore, flow cytometry analysis of a combination treatment of compound 16b and Doxorubicin to the MCF7 cell line revealed an increase in cell cycle arrest at the G2/M phase and a more efficient apoptotic effect than Doxorubicin alone. Furthermore, compound 16b showed no cytotoxicity against normal breast MCF-10A cell line (IC50 = 296.25 µM).
Asunto(s)
Anhidrasa Carbónica IX , Inhibidores de Anhidrasa Carbónica , Anhidrasas Carbónicas , Proliferación Celular , Cumarinas , Relación Dosis-Respuesta a Droga , Doxorrubicina , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/química , Inhibidores de Anhidrasa Carbónica/síntesis química , Cumarinas/farmacología , Cumarinas/química , Cumarinas/síntesis química , Anhidrasa Carbónica IX/antagonistas & inhibidores , Anhidrasa Carbónica IX/metabolismo , Doxorrubicina/farmacología , Células MCF-7 , Anhidrasas Carbónicas/metabolismo , Relación Estructura-Actividad , Estructura Molecular , Proliferación Celular/efectos de los fármacos , Antígenos de Neoplasias/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Hipoxia de la Célula/efectos de los fármacosRESUMEN
Inflammation management presents a critical challenge in modern medicine, with nonsteroidal anti-inflammatory drugs (NSAIDs) being a widely used therapeutic option. However, their efficacy is often accompanied by significant gastrointestinal adverse effects, necessitating the exploration of safer alternatives, particularly through the investigation of cyclooxygenase-2 (COX-2) inhibitors. This study endeavors to address this imperative through the synthesis and evaluation of pyrazoline-phenoxyacetic acid derivatives. Among the synthesized compounds, 6a and 6c emerged as promising candidates, demonstrating potent COX-2 inhibition with IC50 values of 0.03 µM for both and selectivity index = 365.4 and 196.9, respectively. Furthermore, these compounds exhibited efficacy in mitigating formalin-induced edema in male Wistar rats, accompanied by favorable safety profiles upon histological examination of vital organs. Comprehensive safety assessments, including evaluation of creatinine, AST, and ALT enzymatic as well as troponin T and creatine kinase-MB levels, further reinforce the promising attributes of the synthetic candidates. Molecular docking studies endorsed by molecular dynamic simulations corroborate the biological findings, elucidating significant protein-ligand interactions at COX-2 active sites indicative of therapeutic potential.
Asunto(s)
Antiinflamatorios no Esteroideos , Inhibidores de la Ciclooxigenasa 2 , Ciclooxigenasa 2 , Edema , Ratas Wistar , Animales , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Masculino , Ciclooxigenasa 2/metabolismo , Edema/tratamiento farmacológico , Edema/inducido químicamente , Ratas , Relación Estructura-Actividad , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Estructura Molecular , Acetatos/química , Acetatos/farmacología , Acetatos/síntesis química , Simulación del Acoplamiento Molecular , Humanos , Relación Dosis-Respuesta a Droga , Formaldehído , FarmacóforoRESUMEN
Fragment merging approach was applied for the design of thiazole/thiazolidinone clubbed pyrazoline derivatives 5a-e, 6a-c, 7 and 10a-d as dual COX-2 and 5-LOX inhibitors. Compounds 5a, 6a, and 6b were the most potent and COX-2 selective inhibitors (IC50= 0.03-0.06 µM, SI = 282.7-472.9) with high activity against 5-LOX (IC50 = 4.36-4.86 µM), while compounds 5b and 10a were active and selective 5-LOX inhibitors with IC50 = 2.43 and 1.58 µM, respectively. In vivo assay and histopathological examination for most active candidate 6a revealed significant decrease in inflammation with higher safety profile in comparison to standard drugs. Compound 6a exhibited the same orientation and binding interactions as the reference COX-2 and 5-LOX inhibitors (celecoxib and quercetin, respectively). Consequently, compound 6a has been identified as a potential lead for further optimization and the development of safe and effective anti-inflammatory drugs.
Asunto(s)
Antiinflamatorios , Tiazoles , Antiinflamatorios/farmacología , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/química , Diseño de Fármacos , Inhibidores de la Lipooxigenasa/farmacología , Inhibidores de la Lipooxigenasa/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad , Tiazoles/farmacología , Tiazolidinas/farmacología , Pirazoles/química , Pirazoles/farmacologíaRESUMEN
In searching for new molecular drug targets, Carbonic Anhydrases (CAs) have emerged as valuable targets in diverse diseases. CAs play critical functions in maintaining pH and CO2 homeostasis, metabolic pathways, and much more. So, it is becoming attractive for medicinal chemists to design novel inhibitors for this class of enzymes with improved potency and selectivity towards the different isoforms. In the present study, three sets of carboxylic acid derivatives 5a-q, 7a-b and 12a-c were designed, developed and evaluated for the hCA inhibitory effects against hCA I, II, IX and XII. Compounds 5l, 5m, and 5q elicited the highest inhibitory activities against hCA II, IX and XII. In summary, structural rigidification, regioisomerism and structural extension, all played obvious roles in the degree of hCA inhibition. This present work could be a good starting point for the design of more non-classical selective hCA inhibitors as potential targets for several diseases.
Asunto(s)
Inhibidores de Anhidrasa Carbónica , Anhidrasas Carbónicas , Antígenos de Neoplasias/metabolismo , Anhidrasa Carbónica IX/metabolismo , Inhibidores de Anhidrasa Carbónica/química , Anhidrasas Carbónicas/metabolismo , Ácidos Carboxílicos/farmacología , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Currently, the humanity is in a fierce battle against various health-related challenges especially those associated with human malignancies. This created the urge to develop potent and selective inhibitors for tumor cells through targeting specific oncogenic proteins possessing crucial roles in cancer progression and survive. In this respect, new series of pyrazole-thiazol-4-one hybrids (9a-p) were synthesized as potential anticancer agents. All the synthesized molecules exhibited potent antiproliferative actions against breast cancer (BC) T-47D and MDA-MB-231 cell lines with IC50 ranges 3.14-4.92 and 0.62-58.01, respectively. Moreover, the most potent anti-proliferative counterparts 9g and 9k were assessed against EGFR. They displayed nanomolar inhibitory activity, IC50 267 ± 12 and 395 ± 17 nM, respectively. Worth noting, both compounds 9g and 9k induced apoptosis in MDA-MB-231 cells, and resulted in a cell cycle arrest at G2/M phase. Furthermore, an in silico analysis including docking and molecular dynamic simulations was performed.
Asunto(s)
Antineoplásicos , Pirazoles/síntesis química , Antineoplásicos/metabolismo , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Pirazoles/farmacología , Relación Estructura-ActividadRESUMEN
New series of benzenesulfonamide and benzoic acid derivatives were designed and synthesized using tail/dual tail approach to improve potency and selectivity as carbonic anhydrase inhibitors. The synthesized compounds evaluated as CAIs against isoforms hCA I, II, IV and IX with acetazolamide (AAZ) as standard inhibitor. The benzenesulfonamide derivatives 7a-d, 8a-h, 12a-c, 13a and 15a-c showed moderate to potent inhibitory activity with selectivity toward isoform hCA II, especially, compound 13a with (Ki = 7.6 nM), while the benzoic acid analogues 12d-f, 13b and 15d-f didn't show any activity except compounds 12d,f and 15e that showed weak activity. Additionally, molecular docking was performed for compounds 7a, 8a, 8e, 12a, 13a and 15a on isoform hCA I, II to illustrate the possible interaction with the active site to justify the inhibitory activity.
Asunto(s)
Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/metabolismo , Sulfonamidas/farmacología , Sulfonas/farmacología , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Relación Dosis-Respuesta a Droga , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonas/síntesis química , Sulfonas/química , BencenosulfonamidasRESUMEN
In the current medical era, human health is experiencing numerous challenges, particularly the human malignancies. Therefore, the therapeutic arsenal for these malignancies is to be inexorably enhanced with new treatments that target tumor cells in a selective manner. In this regard, the present work aims at developing a new set of small molecules featuring the privileged isatin scaffold conjugated with a thiazolo[3,2-a]benzimidazole (TBI) motif through a cleavable hydrazide linker (7a-e and 10a-i) as potential anticancer CDK2 inhibitors. The large tricyclic TBI motif is anticipated to achieve a plethora of hydrophobic interactions within the CDK2 binding site. The growth of the two examined cell lines was significantly inhibited by most the prepared hybrids with IC50 ranges; (2.60 ± 1.47-20.90 ± 1.17 µM, against MDA-MB-231) and (1.27 ± 0.06-16.83 ± 0.95 µM, against MCF-7). In particular, hybrids 7a, 7d and 10a displayed potent dual activity against the examined cell lines, and thus selected for further investigations. They exerted a significance alteration in the cell cycle progression, in addition to an apoptosis induction within both MDA-MB-231 and MCF-7 cells. Furthermore, 7a, 7d and 10a displayed potent CDK2 inhibitory action (IC50 = 96.46 ± 5.3, 26.24 ± 1.4 and 42.95 ± 2.3 nM, respectively). The docking simulations unveiled, as expected, the ability of the TBI ring to well-accommodate and establish several hydrophobic interactions within a hydrophobic pocket in the CDK2 binding site. Also, the docking simulations highlighted the significance of incorporation of the hydrazide linker and isatin unsubstituted (NH) functionality in the H-bonding interactions. Interestingly, the most potent CDK2 inhibitor 7d achieved the best binding score (-11.2 Kcal/mole) and formed the most stable complex with CDK2 enzyme (RMSD = 1.24 Å) in a 100 ns MD simulation. In addition, the MM-PBSA calculations ascribed the lowest binding free energy to the 7d-CDK2 complex (-323.69 ± 15.17 kJ/mol). This could be attributed to an incorporation of the 5-OCH3 group that was engaged in an extra hydrogen bonding with key THR14 amino acid residue. Finally, these results suggested hybrid 7d as a good candidate for further optimization as promising breast cancer antitumor agent and CDK2 inhibitor.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Quinasa 2 Dependiente de la Ciclina/genética , Quinasa 2 Dependiente de la Ciclina/metabolismo , Diseño de Fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Simulación de Dinámica Molecular , Estructura MolecularRESUMEN
As a front-runner selective CA IX inhibitor currently in Phase Ib/II clinical trials, SLC-0111 has been herein exploited as a lead molecule for development of new different sets of N-phenyl-2-(phenylsulfonyl)acetamides/propanamides incorporating different functionalities; primary sulfonamide (5a-f), free carboxylic (8a, 8d), ethyl ester (8b, 8e), acetyl (8c, 8f) and nitro (10a, 10b), as potential carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. All the prepared analogues have been examined for their CA inhibitory activities towards four human (h) isoenzymes, hCA I, II, IX and XII. Interestingly, replacement of SLC-0111 ureido linker with the flexible sulfonyl acetamide linker, as well as linker branching and elongation strategies successfully enhanced the inhibitory action toward hCA IX isoform, such as in sulfones 5a-d and 5f which displayed better activity than SLC-0111. Furthermore, sulfonamide-based sulfone (5f) and carboxylic acid-based sulfones (8a and 8d) demonstrated interesting selectivity toward the tumor-related hCA IX isoform over both hCA I and hCA II, which suggests them as promising candidates for further development as potential anticancer candidates. Thereafter, the anti-proliferative action for sulfones 5f, 8a and 8d was examined against breast (MCF-7) and colon (HCT-116) cancer cell lines. Also, sulfone 5f was further assessed for its impact on the cell cycle progression and apoptosis in HCT-116 cells.
Asunto(s)
Amidas/farmacología , Antineoplásicos/farmacología , Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/metabolismo , Compuestos de Fenilurea/farmacología , Sulfonamidas/farmacología , Amidas/síntesis química , Amidas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Estructura Molecular , Compuestos de Fenilurea/síntesis química , Compuestos de Fenilurea/química , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/químicaRESUMEN
Mitochondrial anti-apoptotic Bcl2 and BclxL proteins, are overexpressed in multiple tumour types, and has been involved in the progression and survival of malignant cells. Therefore, inhibition of such proteins has become a validated and attractive target for anticancer drug discovery. In this manner, the present studies developed a series of novel isatin-indole conjugates (7a-j and 9a-e) as potential anticancer Bcl2 and BclxL inhibitors. The progression of the two examined colorectal cancer cell lines was significantly inhibited by all of the prepared compounds with IC50 ranges132-611 nM compared to IC50 = 4.6 µM for 5FU, against HT-29 and IC50 ranges 37-468 nM compared to IC50 = 1.5 µM for 5FU, against SW-620. Thereafter, compounds 7c and 7g were selected for further investigations. Interestingly, both compounds exhibited selective cytotoxicity against both cell lines with high safety to normal fibroblast (HFF-1). In addition, both compounds 7c and 7g induced apoptosis and inhibited Bcl2 and BclxL expression in a dose-dependent manner. Collectively, the high potency and selective cytotoxicity suggested that conjugates 7c and 7g could be a starting point for further optimisation to develop novel pro-apoptotic and antitumor agents towards colon cancer.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Desarrollo de Medicamentos , Hidrazinas/farmacología , Indoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias Colorrectales/patología , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Hidrazinas/síntesis química , Hidrazinas/química , Indoles/síntesis química , Indoles/química , Estructura Molecular , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Herein we describe design and synthesis of different series of novel small molecules featuring 3-methylthiazolo[3,2-a]benzimidazole moiety (as a tail) connected to the zinc anchoring benzenesulfonamide moiety via ureido (7), enaminone (12), hydrazone (14), or hydrazide (15) linkers. The newly prepared conjugates have been screened for their inhibitory activities toward four human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms: hCA I, II, IX and XII. Thereafter, the urea and enaminone linkers were elongated by one- or two-atoms spacers to afford the elongated counterparts 9 and 13, respectively. Finally, the zinc anchoring sulfonamide group was replaced by the carboxylic acid group to afford acids 17. Compounds 12d, 13b and 15 displayed single-digit nanomolar CA IX inhibitory activities (KIs = 6.2, 9.7 and 5.5 nM, respectively), along with good selectivity towards hCA IX over hCA I and II. Subsequently, they were screened for their growth inhibitory actions against breast cancer MCF-7 and MDA-MB-231 cell lines, and for their impact on cell cycle progression and induction of apoptosis. Moreover, a molecular docking study was conducted to gain insights for the plausible binding interactions of target sulfonamides within hCA isoforms II, IX and XII binding sites.
Asunto(s)
Bencimidazoles/química , Bencimidazoles/farmacología , Anhidrasas Carbónicas/metabolismo , Diseño de Fármacos , Modelos Moleculares , Sulfonamidas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Bencimidazoles/síntesis química , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/química , Dominio Catalítico , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/química , Isoenzimas/metabolismo , Células MCF-7 , BencenosulfonamidasRESUMEN
As a continuation for our previous work, a novel set of N-alkylindole-isatin conjugates (7, 8a-c, 9 and 10a-e) is here designed and synthesised with the prime aim to develop more efficient isatin-based antitumor candidates. Utilising the SAR outputs from the previous study, our design here is based on appending four alkyl groups with different length (ethyl and n-propyl), bulkiness (iso-propyl) and unsaturation (allyl) on N-1 of indole motif, with subsequent conjugation with different N-unsubstituted isatin moieties to furnish the target conjugates. As planned, the adopted strategy achieved a substantial improvement in the growth inhibitory profile for the target conjugates in comparison to the reported lead VI. The best results were obtained with N-propylindole -5-methylisatin hybrid 8a which displayed broad spectrum anti-proliferative action with efficient sub-panel GI50 (MG-MID) range from 1.33 to 4.23 µM, and promising full-panel GI50 (MG-MID) equals 3.10 µM, at the NCI five-dose assay. Also, hybrid 8a was able to provoke cell cycle disturbance and apoptosis in breast T-47D cells as evidenced by the DNA flow cytometry and Annexin V-FITC/PI assays. Furthermore, hybrid 8a exhibited good inhibitory action against cell cycle regulator CDK2 protein kinase and the anti-apoptotic Bcl-2 protein (IC50= 0.85 ± 0.03 and 0.46 ± 0.02 µM, respectively). Interestingly, molecular docking for hybrid 8a in CDK2 and Bcl-2 active sites unveiled that N-propyl group is involved in significant hydrophobic interactions. Taken together, the results suggested conjugate 8a as a promising lead for further development and optimisation as an efficient antitumor drug.
Asunto(s)
Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Oxindoles/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Simulación por Computador , Quinasa 2 Dependiente de la Ciclina/biosíntesis , Humanos , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesisRESUMEN
Herein we describe the design and synthesis of two series of sulfonamides featuring N-unsubstituted (4a-c) or N-substituted (7a-o) isatin moieties (as tails) connected to benzenesulfonamide moiety via a hydrazine linker. All the prepared sulfonamides (4a-c and 7a-o) showed potent inhibitory activities toward transmembrane tumor-associated human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, IX and XII with KI range (8.3-65.4â¯nM) and (11.9-72.9â¯nM), respectively. Furthermore, six sulfonamides (7e, 7i, 7j, 7m, 7n and 7o) were assessed for their anti-proliferative activity, according to US-NCI protocol, toward a panel of sixty cancer cell lines. Compounds 7j and 7n were the most promising counterparts in this assay displaying broad spectrum anti-proliferative activity toward diverse cell lines. Also, sulfonamide 7n significantly inhibited clonogenicity of HCT-116â¯cells in a concentration dependent manner in the colony forming assay. Moreover, molecular modeling studies were performed to gain insights for the plausible binding interactions and affinities for the target isatin-based sulfonamides (4a-c and 7a-o) within hCA isoforms II and IX active sites.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/metabolismo , Hidrazinas/farmacología , Isatina/farmacología , Sulfonamidas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Hidrazinas/química , Isatina/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Células Tumorales Cultivadas , BencenosulfonamidasRESUMEN
In the presented work, we report the design and synthesis of novel SLC-0111 thiazole and thiadiazole analogues (11a-d, 12a-d, 16a-c and 17a-d). A bioisosteric replacement approach was adopted to replace the 4-fluorophenyl tail of SLC-0111 with thiazole and thiadiazole ones, which were thereafter extended with lipophilic un/substituted phenyl moieties. All the newly synthesized SLC-0111 analogues were evaluated in vitro for their inhibitory activity towards a panel of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms (hCA I, II, IX and XII), using a stopped-flow CO2 hydrase assay. All the examined isoforms were inhibited by the primary sulfonamide derivatives (11a-d and 12a-d) in variable degrees with the following KI ranges: 162.6-7136â¯nM for hCA I, 9.0-833.6â¯nM for hCA II, 7.9-153.0â¯nM for hCA IX, and 9.4-94.0â¯nM for hCA XII. In particular, compounds 12b and 12d displayed 5.5-fold more potent inhibitory activity (KIsâ¯=â¯8.3 and 7.9â¯nM, respectively) than SLC-0111 (KIâ¯=â¯45â¯nM) towards hCA IX. Molecular docking study was carried out for 12d within the hCA IX (PDB 3IAI) active site, to justify its inhibitory activity.
Asunto(s)
Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/metabolismo , Compuestos de Fenilurea/farmacología , Sulfonamidas/farmacología , Tiadiazoles/farmacología , Tiazoles/farmacología , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Relación Dosis-Respuesta a Droga , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Modelos Moleculares , Estructura Molecular , Compuestos de Fenilurea/química , Relación Estructura-Actividad , Sulfonamidas/química , Tiadiazoles/química , Tiazoles/químicaRESUMEN
SLC-0111, an ureido substituted benzenesulfonamide, is a selective carbonic anhydrase (CA, EC 4.2.1.1) IX inhibitor that is currently in Phase I/II clinical trials for the treatment of advanced hypoxic tumors complicated with metastases. Herein we report the synthesis of two series of 3/4-(3-aryl-3-oxopropenyl) aminobenzenesulfonamides 5a-i and 6a-j as SLC-0111 enaminone congeners. The prepared enaminones were in vitro investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, IV and IX, using a stopped-flow CO2 hydrase assay. All these isoforms were inhibited by the enaminones reported here in variable degrees. The target tumor-associated isoform hCA IX was undeniably the most affected one (KIs: 0.21-7.1â¯nM), with 6- to 21-fold enhanced activity than SLC-0111 (KIâ¯=â¯45â¯nM). All the prepared enaminones displayed interesting selectivity towards hCA IX over hCA I (SI: 32 - >35714), hCA II (SI: 2 - 1689) and hCA IV (SI: 11 - >45454). Of particular interest, bioisosteric replacement of phenyl tail with the bulkier 2-naphthyl tail, sulfonamide 6h, achieved the higher II/IX selectivity herein reported with SI of 1689.
Asunto(s)
Compuestos de Anilina/farmacología , Antígenos de Neoplasias/química , Anhidrasa Carbónica IX/química , Inhibidores de Anhidrasa Carbónica/farmacología , Sulfonamidas/farmacología , Compuestos de Anilina/síntesis química , Compuestos de Anilina/química , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Pruebas de Enzimas , Humanos , Cinética , Estructura Molecular , Compuestos de Fenilurea/química , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/químicaRESUMEN
Herein we report the design and synthesis of novel N-substituted isatins-SLC-0111 hybrids (6a-f and 9a-l). A structural extension approach was adopted via N-alkylation and N-benzylation of isatin moiety to enhance the tail hydrophobic interactions within the carbonic anhydrase (CA) IX active site. Thereafter, a hybrid pharmacophore approach was utilized via merging the pharmacophoric elements of isatin and SLC-0111 in a single chemical framework. As planned, a substantial improvement of inhibitory profile of the target hybrids (KIs: 4.7-86.1â¯nM) towards hCA IX in comparison to N-unsubstituted leads IVa-c (KIs: 192-239â¯nM), was achieved. Molecular docking of the designed hybrids in CA IX active site unveiled, as planned, the ability of N-alkylated and N-benzylated isatin moieties to accommodate in a wide hydrophobic pocket formed by T73, P75, P76, L91, L123 and A128, establishing strong van der Waals interactions. Hybrid 6c displayed good anti-proliferative activity under hypoxic conditions towards breast cancer MDA-MB-231 and MCF-7â¯cell lines (IC50â¯=â¯7.43⯱â¯0.28 and 12.90⯱â¯0.34⯵M, respectively). Also, 6c disrupted the MDA-MB-231â¯cell cycle via alteration of the Sub-G1 phase and arrest of G2-M stage. Additionally, 6c displayed significant increase in the percent of annexinV-FITC positive apoptotic cells from 1.03 to 18.54%. Furthermore, 6c displayed potent VEGFR-2 inhibitory activity (IC50â¯=â¯260.64â¯nM). Collectively, these data suggest 6c as a promising lead molecule for the development of effective anticancer agents.
Asunto(s)
Antineoplásicos/química , Anhidrasa Carbónica IX/metabolismo , Inhibidores de Anhidrasa Carbónica/química , Isatina/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Sitios de Unión , Anhidrasa Carbónica IX/química , Inhibidores de Anhidrasa Carbónica/farmacología , Dominio Catalítico , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Isatina/química , Simulación del Acoplamiento Molecular , Compuestos de Fenilurea/farmacología , Unión Proteica , Sulfonamidas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
In connection with our research program on the development of novel anti-tubercular candidates, herein we report the design and synthesis of two different sets of indole-thiazolidinone conjugates (8a,b; 11a-d) and (14a-k; 15a-h). The target compounds were evaluated for their in vitro antibacterial and antifungal activities against selected human pathogens viz. Staphylococcus aureus (Gram positiveve), Pseudomonas aeruginosa, Escherichia coli (Gram negative), Mycobacterium tuberculosis (Acid-fast bacteria), Aspergillus fumigates and Candida albicans (fungi). Moreover, eukaryotic cell-toxicity was tested via an integrated ex vivo drug screening model in order to evaluate the selective therapeutic index (SI) towards antimicrobial activity when microbes are growing inside primary immune cells. Also, the cytotoxicity towards a panel of cancer cell lines and human lung fibroblast normal cell line, WI-38â¯cells, was explored to assure their safety. Compound 15b emerged as a hit in this study with potent broad spectrum antibacterial (MIC: 0.39-0.98⯵g/mL) and antifungal (MIC: 0.49-0.98⯵g/mL) activities, in addition to its ability to kill mycobacteria M. aurum inside an infected macrophage model with good therapeutic window. Moreover, compound 15b displayed promising activity towards resistant bacteria strains MRSA and VRE with MIC values equal 3.90 and 7.81⯵g/mL, respectively. These results suggest compound 15b as a new therapeutic lead with good selectivity for further optimization and development.
Asunto(s)
Antibacterianos/farmacología , Antifúngicos/farmacología , Bacterias/efectos de los fármacos , Hongos/efectos de los fármacos , Indoles/farmacología , Tiazolidinas/farmacología , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Antifúngicos/síntesis química , Antifúngicos/química , Línea Celular , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Indoles/química , Macrófagos/efectos de los fármacos , Macrófagos/microbiología , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Fenotipo , Células RAW 264.7 , Relación Estructura-Actividad , Tiazolidinas/químicaRESUMEN
As a part of our ongoing efforts towards developing novel carbonic anhydrase inhibitors based on the isatin moiety, herein we report the synthesis and biological evaluation of novel sulfonamides (5a-h, 10a-g and 11a-c) incorporating substituted 2-indolinone moiety (as tail) linked to benzenesulfonamide (as zinc anchoring moiety) through a hydrazide linker. The synthesized sulfonamides were evaluated in vitro for their inhibitory activity against the following human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, hCA I, II, IX and XII. All these isoforms were inhibited by the sulfonamides reported here in variable degrees. hCA I was inhibited with KIs in the range of 671.8: 3549.5â¯nM, hCA II in the range of 36.8: 892.4â¯nM; hCA IX in the range of 8.9: 264.5â¯nM, whereas hCA XII in the range of 9.0: 78.1â¯nM. In particular, compound 10b emerged as a single-digit nanomolar hCA IX and XII inhibitor (8.9 and 9.2â¯nM, respectively). Molecular docking studies carried out for compound 10b within the hCA II, IX and XII active sites allowed us to rationalize the obtained inhibition results.
Asunto(s)
Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/metabolismo , Isatina/farmacología , Sulfonamidas/farmacología , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Relación Dosis-Respuesta a Droga , Humanos , Isatina/química , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Sulfonamidas/química , BencenosulfonamidasRESUMEN
AIM: Mycobacterium tuberculosis, which causes tuberculosis, continues to infect millions of the global population, resulting in 1.8 million deaths worldwide in 2015. METHODOLOGY: Hybrids of 2-amino-4-methylthiazole bearing 5-acetyl/5-ethyl carboxylate functionality with 5-arylidene thiazolidinone moiety (6a-k and 9a-d) were synthesized and screened for antitubercular and antimicrobial activities. RESULTS & DISCUSSION: 5-ethyl carboxylate derivative 6k revealed half antitubercular activity (minimal inhibitory concentration = 1.56 µg/ml) than the acetyl analog 6c (minimal inhibitory concentration = 0.78 µg/ml), however, it exhibited more potent broad spectrum antibacterial and antifungal activities in addition to its excellent safety profile with high selectivity toward M. tuberculosis over normal human lung cells. Collectively, these data suggested that compound 6k can be considered as an ideal lead compound for further optimization.
Asunto(s)
Antituberculosos/química , Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Tiazoles/química , Tiazoles/farmacología , Tiazolidinas/química , Tiazolidinas/farmacología , Antituberculosos/síntesis química , Línea Celular , Diseño de Fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazolidinas/síntesis química , Tuberculosis/tratamiento farmacológicoRESUMEN
On account of their significance as apoptosis inducing agents, merging indole and 3-hydrazinoindolin-2-one scaffolds is a logic tactic for designing pro-apoptotic agents. Consequently, 27 hybrids (6a-r, 9a-f and 11a-c) were synthesised and evaluated for their cytotoxicity against MCF-7, HepG-2 and HCT-116 cancer cell lines. SAR studies unravelled that N-propylindole derivatives were the most active compounds such as 6n (MCF-7; IC50=1.04 µM), which displayed a significant decrease of cell population in the G2/M phase and significant increase in the early and late apoptosis by 19-folds in Annexin-V-FTIC assay. Also, 6n increased the expression of caspase-3, caspase-9, cytochrome C and Bax and decreased the expression of Bcl-2. Moreover, compounds 6i, 6j, 6n and 6q generated ROS by significant increase in the level of SOD and depletion of the levels of CAT and GSH-Px in MCF-7.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Diseño de Fármacos , Hidrazonas/farmacología , Indoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Células Hep G2 , Humanos , Hidrazonas/síntesis química , Hidrazonas/química , Indoles/síntesis química , Indoles/química , Células MCF-7 , Estructura Molecular , Estrés Oxidativo/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Herein we report the synthesis of two series of novel 4/3-((4-oxo-5-(2-oxoindolin-3-ylidene)thiazolidin-2-ylidene)amino)benzenesulfonamides (4a-m and 7a-g). All the newly prepared sulfonamides were in vitro investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, IV and IX, using a stopped-flow CO2 hydrase assay. In particular, hCA isoforms II and IX (tumor-associated) were more susceptible to inhibition by the synthesized derivatives, with KIs in the range of 2.6-598.2 nM for hCA II, and of 16.1-321 nM for hCA IX. All compounds (4a-m and 7a-g) were evaluated for their anti-proliferative activity against breast cancer MCF-7 and colorectal cancer Caco-2 cell lines. Compound 4c was found to be the most potent derivative against MCF-7 (IC50 = 3.96 ± 0.21 µM), while 4j was the most active member against Caco-2 cells (IC50 = 5.87 ± 0.37 µM). Compound 4c induced the intrinsic apoptotic mitochondrial pathway in MCF-7 cells; evidenced by the enhanced expression of the pro-apoptotic protein Bax and the reduced expression of the anti-apoptotic protein Bcl-2, and the up-regulated active caspase-9 and caspase-3 levels.