RESUMEN
Dual targeting by a single molecule has emerged as a promising strategy for fighting cancer. In this study, a new set of 2-thioquinazolin-4(3H)-ones as potential anti-cancer surrogates endowed with dual EGFR/VEGFR-2 kinases inhibitory activities were synthesized. The anti-tumor potency of the newly synthesized candidates 4-27 was evaluated against a panel of four cancer cell lines. The prepared candidates 4-27 showed comparable activity to that of the standard drug sorafenib. For instance, compound 4 (IC50 = 1.50-5.86 µM) and compound 20 (IC50 = 4.42-6.39 µM) displayed superior potencies against all cell lines compared to sorafenib (IC50 = 5.47-7.26 µM). Dual EGFR/VEGFR-2 inhibitory activities of the most active analogues (4, 11, and 20) were investigated. Compound 4 showed comparable EGFR/VEGFR-2 inhibitory activity to the used control drugs. Flow cytometric analysis indicates that the most potent analogue 4 stopped the cell cycle at the G1 phase and induced 46.53% total apoptosis in HCT-116 cells that was much more powerful than the untreated cells with 2.15% apoptosis. Molecular docking and dynamic simulations of 4, 11, and 20 with EGFR and VEGFR-2 were performed to examine the binding mode and interaction within the enzyme binding pockets.
RESUMEN
Organic halogen compounds are cornerstones of applied chemical sciences. Halogen substitution is a smart molecular design strategy adopted to influence reactivity, membrane permeability and receptor interaction. Chiral bioreceptors may restrict the stereochemical requirements in the halo-ligand design. Straightforward (but expensive) catalyzed stereospecific halogenation has been reported. Historically, PCl5 served access to uncatalyzed stereoselective chlorination although the stereochemical outcomes were influenced by steric parameters. Nonetheless, stereochemical investigation of PCl5 reaction mechanism with carbamoyl (RCONHX) compounds has never been addressed. Herein, we provide the first comprehensive stereochemical mechanistic explanation outlining halogenation of carbamoyl compounds with PCl5; the key regioselectivity-limiting nitrilimine intermediate (8-Z.HCl); how substitution pattern influences regioselectivity; why oxadiazole byproduct (P1) is encountered; stereo-electronic factors influencing the hydrazonoyl chloride (P2) production; and discovery of two stereoselectivity-limiting parallel mechanisms (stepwise and concerted) of elimination of HCl and POCl3. DFT calculations, synthetic methodology optimization, X-ray evidence and experimental reaction kinetics study evidence all supported the suggested mechanism proposal (Scheme 2). Finally, we provide mechanism-inspired future recommendations for directing the reaction stereoselectivity toward elusive and stereochemically inaccessible (E)-bis-hydrazonoyl chlorides along with potentially pivotal applications of both (E/Z)-stereoisomers especially in medicinal chemistry and protein modification.
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Cancer remains a leading cause of death worldwide, often resulting from uncontrolled growth in various organs. Protein kinase inhibitors represent an important class of targeted cancer therapies. Recently, the kinases BRAF and VEGFR-2 have shown synergistic effects on tumor progression. Seeking to develop dual BRAF/VEGFR-2 inhibitors, we synthesized 18 amino-benzothiazole derivatives with structural similarities to reported dual inhibitors. Four compounds-4a, 4f, 4l, and 4r-demonstrated remarkable cytotoxicity, with IC50 values ranging from 3.58 to 15.36 µM, against three cancer cell lines. Furthermore, these compounds showed IC50 values of 38.77-66.22 µM in the case of a normal cell line, which was significantly safer than the reference, sorafenib. Subsequent investigation revealed that compound 4f exhibited the capacity to inhibit the BRAF and VEGFR-2 enzymes, with IC50 values similar to sorafenib (0.071 and 0.194 µM, respectively). Moreover, compound 4f caused G2-M- and S-phase cycle arrest. Molecular modeling demonstrated binding patterns compatible with inhibition for both targets, where 4f exerted the critical interactions in the BRAF site and interacted in the VEGFR-2 site in a manner akin to sorafenib, demonstrating affinity similar to dabrafenib.
Asunto(s)
Antineoplásicos , Benzotiazoles , Proliferación Celular , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas B-raf , Tiadiazoles , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Humanos , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Benzotiazoles/química , Benzotiazoles/farmacología , Benzotiazoles/síntesis química , Tiadiazoles/química , Tiadiazoles/farmacología , Tiadiazoles/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Diseño de Fármacos , Relación Estructura-Actividad , Sorafenib/farmacología , Sorafenib/química , Estructura Molecular , Simulación por Computador , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
Cisplatin is a potent compound in anti-tumor chemotherapy; however, its clinical utility is hampered by dose-limiting nephrotoxicity. This study investigated whether papaverine could mitigate cisplatin-induced kidney damage while preserving its chemotherapeutic efficacy. Integrative bioinformatics analysis predicted papaverine modulation of the mechanistic pathways related to cisplatin renal toxicity; notably, mitogen-activated protein kinase 1 (MAPK1) signaling. We validated protective effects in normal kidney cells without interfering with cisplatin cytotoxicity on a cancer cell line. Concurrent in vivo administration of papaverine alongside cisplatin in rats prevented elevations in nephrotoxicity markers, including serum creatinine, blood urea nitrogen, and renal oxidative stress markers (malondialdehyde, inducible nitric oxide synthase (iNOS), and pro-inflammatory cytokines), as tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein 1 (MCP-1), and interleukin-6 (IL-6). Papaverine also reduced apoptosis markers such as Bcl2 and Bcl-2-associated X protein (Bax) and kidney injury molecule-1 (KIM-1), and histological damage. In addition, it upregulates antioxidant enzymes like catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) while boosting anti-inflammatory signaling interleukin-10 (IL-10). These effects were underlined by the ability of Papaverine to downregulate MAPK-1 expression. Overall, these findings show papaverine could protect against cisplatin kidney damage without reducing its cytotoxic activity. Further research would allow the transition of these results to clinical practice.
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Cisplatino , Inflamación , Estrés Oxidativo , Papaverina , Cisplatino/efectos adversos , Papaverina/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Ratas , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/inducido químicamente , Humanos , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Masculino , Apoptosis/efectos de los fármacos , Antineoplásicos/farmacología , Sustancias Protectoras/farmacología , Antioxidantes/farmacología , Citocinas/metabolismo , Simulación por Computador , BiomarcadoresRESUMEN
In our study, a series of quinazoline-1,2,3-triazole hybrids (14a-r) have been designed and synthesized as multi-target EGFR, VEGFR-2, and Topo II inhibitors. All synthesized hybrids were assessed for their anticancer capacity. MTT assay revealed that compounds 14a, 14d, and 14k were the most potent hybrids against four cancer cell lines, HeLa, HePG-2, MCF-7, and HCT-116 at low micromolar range while exhibiting good selectivity against normal cell line WI-38. Sequentially, the three compounds were evaluated for EGFR, VEGFR-2, and Topo II inhibition. Compound 14d was moderate EGFR inhibitor (IC50 0.103 µM) compared to Erlotinib (IC50 0.049 µM), good VEGFR-2 inhibitor (IC50 0.069 µM) compared to Sorafenib (IC50 0.031 µM), and stronger Topo II inhibitor (IC50 19.74 µM) compared to Etoposide (IC50 34.19 µM) by about 1.7 folds. Compounds 14k and 14a represented strong inhibitory activity against Topo II with (IC50 31.02 µM and 56.3 µM) respectively, compared to Etoposide. Additionally, cell cycle analysis and apoptotic induction were performed. Compound 14d arrested the cell cycle on HeLa at G2/M phase by 17.53 % and enhanced apoptosis by 44.08 %. A molecular Docking study was implemented on the three hybrids and showed proper binding interaction with EGFR, VEGFR-2, and Topo II active sites.
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Antineoplásicos , Proliferación Celular , ADN-Topoisomerasas de Tipo II , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB , Simulación del Acoplamiento Molecular , Triazoles , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Triazoles/química , Triazoles/farmacología , Triazoles/síntesis química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Relación Estructura-Actividad , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Proliferación Celular/efectos de los fármacos , Estructura Molecular , ADN-Topoisomerasas de Tipo II/metabolismo , Quinazolinas/farmacología , Quinazolinas/química , Quinazolinas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Inhibidores de Topoisomerasa II/farmacología , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa II/síntesis químicaRESUMEN
In an effort to develop new compounds for managing drug-induced liver injury, we prepared 23 novel hybrids based on 3-acetyl-11-keto-ß-boswellic acid (AKBA) using various biocompatible linkers. A bioguided approach was employed to identify the most promising hybrid. Eight compounds exhibited superior anti-inflammatory activity compared to the parent compound. Two of these hybrids (5b and 18) were able to reduce gene expression of TNF-α in LPS-induced inflammation in RAW 264.7 cells, similar to dexamethasone. Subsequently, the hepatoprotective potential of these hybrids was evaluated against acetaminophen (APAP) toxicity in HepG2 cells at doses of 1 and 10 µM. Both hybrids effectively restored cytokine levels, which had been elevated by APAP, to normal levels. Furthermore, they normalized depleted superoxide dismutase and reduced glutathione levels while significantly reducing malondialdehyde (MDA) levels. Network pharmacology analysis suggested that AKBA-based hybrids exert their action by regulating PI3K and EGFR pathways, activating anti-inflammatory mechanisms, and initiating tissue repair and regeneration. Molecular docking studies provided insights into the interaction of the hybrids with PI3K. Additionally, the hybrids demonstrated good stability at different pH levels, following first-order kinetics, with relatively long half-lives, suggesting potential for absorption into circulation without significant degradation.
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In this study, we investigated the conjugation of theophylline with different compounds of natural origin hoping to construct new hybrids with dual activity against cholinergic and inflammatory pathways as potential agents for the treatment of Alzheimer's disease (AD). Out of 28 tested hybrids, two hybrids, acefylline-eugenol 6d and acefylline-isatin 19, were able to inhibit acetylcholinesterase (AChE) at low micromolar concentration displaying IC50 values of 1.8 and 3.3 µM, respectively, when compared to the galantamine standard AChE inhibitor. Moreover, the prepared hybrids exhibited a significant anti-inflammatory effect against lipopolysaccharide induced inflammation in RAW 264.7 and reduced nitric oxide (NO), tumor necrosis alpha (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) levels in a dose dependent manner. These hybrids demonstrated significant reductions in nitric oxide (NO), tumor necrosis alpha (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) levels in RAW 264.7 cells induced by lipopolysaccharide (LPS). The findings of this study were further explained in light of network pharmacology analysis which suggested that AChE and nitric oxide synthase were the main targets of the most active compounds. Molecular docking studies revealed their ability to bind to the heme binding site of nitric oxide synthase 3 (NOS-3) and effectively occupy the active site of AChE, interacting with both the peripheral aromatic subsite and catalytic triad. Finally, the compounds demonstrated stability in simulated gastric and intestinal environments, suggesting potential absorption into the bloodstream without significant hydrolysis. These findings highlight the possible therapeutic potential of acefylline-eugenol 6d and acefylline-isatin 19 hybrids in targeting multiple pathological mechanisms involved in AD, offering promising avenues for further development as potential treatments for this devastating disease.
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This research study describes the development of new small molecules based on 2,4-thiazolidinedione (2,4-TZD) and their aldose reductase (AR) inhibitory activities. The synthesis of 17 new derivatives of 2,4-TZDs hybrids was feasible by incorporating two known bioactive scaffolds, benzothiazole heterocycle, and nitro phenacyl moiety. The most active hybrid (8b) was found to inhibit AR in a non-competitive manner (0.16 µM), as confirmed by kinetic studies and molecular docking simulations. Furthermore, the in vivo experiments demonstrated that compound 8b had a significant hypoglycaemic effect in mice with hyperglycaemia induced by streptozotocin. Fifty milligrams per kilogram dose of 8b produced a marked decrease in blood glucose concentration, and a lower dose of 5 mg/kg demonstrated a noticeable antihyperglycaemic effect. These outcomes suggested that compound 8b may be used as a promising therapeutic agent for the treatment of diabetic complications.
Asunto(s)
Aldehído Reductasa , Hipoglucemiantes , Animales , Ratones , Aldehído Reductasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Hipoglucemiantes/farmacología , Cinética , Simulación del Acoplamiento Molecular , Tiazolidinas/farmacologíaRESUMEN
SARS-CoV-2 pandemic in the end of 2019 led to profound consequences on global health and economy. Till producing successful vaccination strategies, the healthcare sectors suffered from the lack of effective therapeutic agents that could control the spread of infection. Thus, academia and the pharmaceutical sector prioritise SARS-CoV-2 antiviral drug discovery. Here, we exploited previous reports highlighting the anti-SARS-CoV-2 activities of isatin-based molecules to develop novel triazolo-isatins for inhibiting main protease (Mpro) of the virus, a crucial enzyme for its replication in the host cells. Particularly, sulphonamide 6b showed promising inhibitory activity with an IC50= 0.249 µM. Additionally, 6b inhibited viral cell proliferation with an IC50 of 4.33 µg/ml, and was non-toxic to VERO-E6 cells (CC50 = 564.74 µg/ml) displaying a selectivity index of 130.4. In silico analysis of 6b disclosed its ability to interact with key residues in the enzyme active site, supporting the obtained in vitro findings.
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COVID-19 , Isatina , Humanos , SARS-CoV-2 , Sulfanilamida , Sulfonamidas/farmacologíaRESUMEN
The low amount of metabolites isolated from natural products is one of the challenges preventing their biological evaluation. The modulation of biosynthetic pathways by stimulating stress-induced responses in plants was proven to be a valuable tool for diversification of already known natural products. Recently, we reported the dramatic effect of methyl jasmonate (MeJA) on Vinca minor alkaloids distribution. In this study, three compounds identified as 9-methoxyvincamine, minovincinine, and minovincine are successfully isolated in good yield and subjected to several bioassays based on a network pharmacology study. The extracts and isolated compounds show weak to moderate antimicrobial and cytotoxic activities. Also, they are found to significantly promote wound healing in scratch assay, and transforming growth factor-ß (TGF-ß) modulation is suggested to be the potential pathway based on bioinformatic analysis. Hence, Western blotting is used to assess the expression of several markers related to this pathway and wound healing. The extracts and isolated compounds are able to increase the expression of Smad3 and Phosphatidylinositol-3-kinase (PI3K), while downregulating the levels of cyclin D1 and the mammalian target of rapamycin (mTOR) except for minovincine, which increases the mTOR expression, inferring that it might act through a different mechanism. Molecular docking is used to give insights on the ability of isolated compounds to bind with different active sites in mTOR. Collectively, the integrated phytochemical, in silico, and molecular biology approach reveal that V. minor and its metabolite could be repurposed for the management of dermatological disorders where these markers are dysregulated, which opens the gate to develop new therapeutics in the future.
Asunto(s)
Alcaloides , Vinca , Vinca/química , Vinca/metabolismo , Simulación del Acoplamiento Molecular , Alcaloides/farmacología , Alcaloides/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Multi-target inhibitors represent useful anticancer agents with superior therapeutic attributes. Here in, two novel series of benzimidazole-triazole hybrids were designed, synthesised as multi-target EGFR, VEGFR-2 and Topo II inhibitors, and evaluated for anticancer activity. Compounds 5a and 6g were the most potent analogues against four cancer cell lines, HepG-2, HCT-116, MCF-7 and HeLa, and were further evaluated for EGFR, VEGFR-2, and Topo II inhibition. Compound 5a was especially good inhibitor for EGFR (IC50 = 0.086 µM) compared to Gefitinib (IC50 = 0.052 µM), moderate VEGFR-2 inhibitor (IC50 = 0.107 µM) compared to Sorafenib (IC50 = 0.0482 µM), and stronger Topo II inhibitor (IC50 = 2.52 µM) than Doxorubicin (IC50 = 3.62 µM). Compound 6g exhibited moderate EGFR and VEGFR-2 inhibition and weaker Topo II inhibition. DNA binding assay, cell cycle analysis, apoptotic induction, molecular docking, and physicochemical studies were additionally implemented to explore the plausible mechanism of the active compounds.
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Antineoplásicos , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Estructura Molecular , Relación Estructura-Actividad , Simulación del Acoplamiento Molecular , Triazoles/farmacología , Proliferación Celular , Antineoplásicos/farmacología , Antineoplásicos/química , Receptores ErbB/metabolismo , Bencimidazoles/farmacología , Bencimidazoles/química , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
A new series of 2-aminobenzothiazole hybrids linked to thiazolidine-2,4-dione 4a-e, 1,3,4-thiadiazole aryl urea 6a-d, and cyanothiouracil moieties 8a-d was synthesised. The in vitro antitumor effect of the new hybrids was assessed against three cancer cell lines, namely, HCT-116, HEPG-2, and MCF-7 using Sorafenib (SOR) as a standard drug. Among the tested compounds, 4a was the most potent showing IC50 of 5.61, 7.92, and 3.84 µM, respectively. Furthermore, compounds 4e and 8a proved to have strong impact on breast cancer cell line with IC50 of 6.11 and 10.86 µM, respectively. The three compounds showed a good safety profile towards normal WI-38 cells. Flow cytometric analysis of the three compounds in MCF-7 cells revealed that compounds 4a and 4c inhibited cell population in the S phase, whereas 8a inhibited the population in the G1/S phase. The most promising compounds were subjected to a VEGFR-2 inhibitory assay where 4a emerged as the best active inhibitor of VEGFR-2 with IC50 91 nM, compared to 53 nM for SOR. In silico analysis showed that the three new hybrids succeeded to link to the active site like the co-crystallized inhibitor SOR.
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Antineoplásicos , Humanos , Antineoplásicos/farmacología , Benzotiazoles/farmacología , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Células MCF-7 , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas/farmacología , Sorafenib/farmacología , Relación Estructura-Actividad , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
In this work, the natural piperine moiety was utilised to develop two sets of piperine-based amides (5a-i) and ureas (8a-y) as potential anticancer agents. The anticancer action was assessed against triple negative breast cancer (TNBC) MDA-MB-231, ovarian A2780CP and hepatocellular HepG2 cancer cell lines. In particular, 8q stood out as the most potent anti-proliferative analogue against TNBC MDA-MB-231 cells with IC50 equals 18.7 µM, which is better than that of piperine (IC50 = 47.8 µM) and 5-FU (IC50 = 38.5 µM). Furthermore, 8q was investigated for its possible mechanism of action in MDA-MB-231 cells via Annexin V-FITC apoptosis assay and cell cycle analysis. Moreover, an in-silico analysis has proposed VEGFR-2 as a probable enzymatic target for piperine-based derivatives, and then has explored the binding interactions within VEGFR-2 active site (PDB:4ASD). Finally, an in vitro VEGFR-2 inhibition assay was performed to validate the in silico findings, where 8q showed good VEGFR-2 inhibitory activity with IC50 = 231 nM.
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Alcaloides/farmacología , Amidas/farmacología , Antineoplásicos/farmacología , Benzodioxoles/farmacología , Piperidinas/farmacología , Alcamidas Poliinsaturadas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Urea/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Alcaloides/química , Amidas/síntesis química , Amidas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Benzodioxoles/química , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Piperidinas/química , Alcamidas Poliinsaturadas/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Urea/análogos & derivados , Urea/química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Twenty-five new hits of spirooxindole analogs 8a-y engrafted with indole and pyrazole scaffolds were designed and constructed via a [3+2]cycloaddition (32CA) reaction starting from three components: new chalcone-based indole and pyrazole scaffolds 5a-d, substituted isatins 6a-c, and secondary amines 7a-d. The potency of the compounds were assessed in modulating cholinesterase (AChE) activity using Ellman's method. Compounds 8i and 8y showed the strongest acetylcholine esterase inhibition (AChEI) with IC50 values of 24.1 and 27.8 µM, respectively. Molecular docking was used to study their interaction with the active site of hAChE.
RESUMEN
The natural product piperine, the major bioactive alkaloid present in black pepper fruits, has the ability to modulate the functional activity of several biological targets. In this study, we have utilized the natural piperine as a tail moiety to develop new SLC-0111 analogues (6a-d, 8 and 9) as potential carbonic anhydrase inhibitors. Thereafter, different functionalities, free carboxylic acid (11a-c), acetyl (13a) and ethyl ester (13b-c), were exploited as bioisosteres of the sulfamoyl functionality. All piperine-based derivatives were assessed for their inhibitory actions against four human (h) CA isoforms: hCA I, II, IX and XII. The best hCA inhibitory activity was observed for the synthesized primary piperine-sulfonamides (6a-d and 8). In particular, both para-regioisomers (6c and 8) emerged as the most potent hCA inhibitors in this study with two-digit nanomolar activity against hCA II (KIs = 93.4 and 88.6 nM, respectively), hCA IX (KIs = 38.7 and 68.2 nM, respectively), and hCA XII (KIs = 57.5 and 45.6 nM, respectively). Moreover, piperine-sulfonamide 6c was examined for its anti-cancer and pro-apoptotic actions towards breast MCF-7 cancer cell line. Collectively, piperine-based sulfonamides could be considered as a promising scaffold for development of efficient anticancer candidates with potent CA inhibitory activities.
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Antineoplásicos/farmacología , Productos Biológicos/farmacología , Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/metabolismo , Ácidos Carboxílicos/farmacología , Diseño de Fármacos , Sulfonamidas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Productos Biológicos/síntesis química , Productos Biológicos/química , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/química , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Células MCF-7 , Estructura Molecular , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/químicaRESUMEN
Eleven compounds were isolated from the ethyl acetate extract of Cocos nucifera L endocarp, jezonofol 1, scirpusin A 2, cassigarol G 3, maackin A 4, threoguiacyl glycerol-8'-vanillic acid ether 5, erythroguiacyl glycerol-8'-vanillic acid ether 6, apigenin-7-O-ß-D-glucoside 7, piceatannol 8, p-hydroxy-benzoic acid 9, protocatechuic acid 10 and vanillic acid 11. Compounds 1-7 were isolated for the first time from the plant. The isolated compounds were virtually screened against four critical components of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), the main protease (Mpro), papain-like protease (PLpro), nonstructural protein 13 (nsp13) and RNA dependent RNA polymerase (RdRp). Stilbene dimers 1-4 showed remarkable binding affinities towards the investigated targets (binding energy <-7.6 kcal/mol). Compounds 1, 3 and 4 interacted with the catalytic dyad (Cys145-His41) at the active pocket of Mpro which is essential for achieving good inhibitory activity. Compounds 1-3 showed molecular interaction with the conserved ubiquitin-specific protease residues of PLpro, responsible for binding ability at different active sites of nsp13, which are crucial for decreasing the resistance caused by viral immune evasion. Compounds 2 and 3 showed the ability to bind at different active sites of nsp13, which is a key binding site for reducing antiviral resistance. Finally, compounds 1-3 showed the ability to bind with RdRp before and after RNA binding. Our findings suggested that the dimeric stilbene skeleton is a promising candidate for developing anti-COVID-19 drugs. Particularly, 1, 2 and 3, showed a promiscuity pattern binding to multiple targets of SARS-CoV-2 replication. Herein, 20 ns molecular dynamics (MD) simulations combined with molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations were performed to estimate the binding affinity of the most potent three compounds against the viral SARS-CoV-2 targets. MM-GBSA calculations unveiled the outshine potency of compound 1 towards PLpro with a binding energy of -60.7 kcal/mol. Structural and energetic analyses over 20 ns MD simulation displayed the high stability of compound 1 in complex with PLpro. The list of the compounds was considered herein forms a primer for clinical investigation in COVID-19 patients and directing for further antiviral examinations. Drug likeness properties of compounds 1-4 were evaluated.
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Curcumin is a natural compound that has many medical applications. However, its low solubility and poor stability could impede its clinical applications. The present study aimed to formulate dry proniosomes to overcome these pitfalls and improve the therapeutic efficacy of Curcumin. Curcumin-loaded proniosomes were fabricated by the slurry method according to 32 factorial design using Design-Expert software to demonstrate the impact of different independent variables on entrapment efficiency (EE%) and % drug released after 12 h (Q12h). The optimized formula (F5) was selected according to the desirability criteria. F5 exhibited good flowability and appeared, after reconstitution, as spherical nanovesicles with EE% of 89.94 ± 2.31% and Q12h of 70.89 ± 1.62%. F5 demonstrated higher stability and a significant enhancement of Q12h than the corresponding niosomes. The docking study investigated the ability of Curcumin to bind effectively with the active site of DNA polymerase of Herpes simplex virus (HSV). The antiviral activity and the safety of F5 were significantly higher than Curcumin. F5 improved the safety of Acyclovir (ACV) and reduced its effective dose that produced a 100% reduction of viral plaques. Proniosomes could be promising stable carriers of Curcumin to be used as a safe and efficient antiviral agent.
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Antivirales/farmacología , Curcumina/farmacología , Sistemas de Liberación de Medicamentos , Herpes Simple/tratamiento farmacológico , Liposomas/administración & dosificación , Nanopartículas/administración & dosificación , Simplexvirus/efectos de los fármacos , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Antivirales/química , Chlorocebus aethiops , Curcumina/química , Herpes Simple/inducido químicamente , Técnicas In Vitro , Liposomas/química , Nanopartículas/química , Células VeroRESUMEN
In the present study, we report the design and synthesis of novel CAN508 sulfonamide-based analogues (4, 8a-e, 9a-h and 10a-e) as novel carbonic anhydrase (CA) inhibitors with potential CDK inhibitory activity. A bioisosteric replacement approach was adopted to replace the phenolic OH of CAN508 with a sulfamoyl group to afford compound 4. Thereafter, a ring-fusion approach was utilized to furnish the 5/5 fused imidazopyrazoles 8a-e which were subsequently expanded to 6/5 pyrazolopyrimidines 9a-h and 10a-e. All the synthesized analogues were evaluated for their inhibitory activity toward isoforms hCA I, II, IX and XII. The target tumor-associated isoforms hCA IX and XII were effectively inhibited with KIs ranges 6-67.6 and 10.1-88.6 nM, respectively. Furthermore, all compounds were evaluated for their potential CDK2 and 9 inhibitory activities. Pyrazolopyrimidines 9d, 9e and 10b displayed weak CDK2 inhibitory activity (IC50 = 6.4, 8.0 and 11.6 µM, respectively), along with abolished CDK9 inhibitory activity. This trend suggested that pyrazolopyrimidine derivatives merit further optimization to furnish more effective CDK2 inhibitor lead. On account of their excellent activity and selectivity towards hCA IX and XII, pyrazolopyrimidines 10 were evaluated for their anti-proliferative activity toward breast cancer MCF-7 and MDA-MB-468 cell lines under normoxic and hypoxic conditions. The most potent anti-proliferative agents 10a, 10c and 10d significantly increased cell percentage at sub-G1 and G2-M phases with concomitant decrease in the S phase population in MCF-7 treated cells. Finally, a docking study was undertaken to investigate the binding mode for the most selective hCA IX and XII inhibitors 10a-e, within hCA II, IX and XII active sites.
Asunto(s)
Antineoplásicos/farmacología , Compuestos Azo/química , Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/química , Diseño de Fármacos , Neoplasias/tratamiento farmacológico , Pirazoles/química , Antineoplásicos/química , Inhibidores de Anhidrasa Carbónica/química , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Técnicas In Vitro , Simulación del Acoplamiento Molecular , Estructura Molecular , Neoplasias/patología , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
BACKGROUND AND AIM: Traditional medicine is an important source for drug discovery. However, many challenges face the scientific community to develop novel drugs from it. To investigate the rationale behind the medical legacy of centuries of precious knowledge from traditional medicine, we aimed at performing virtual screening to identify potential leads from the middle-age textbook, The Canon of Medicine. EXPERIMENTAL PROCEDURE: A database of chemical constituents of plants mentioned within the book was built and docked against different molecular targets associated with inflammation such as phospholipase A2, p38 alpha mitogen activated protein kinase, cyclooxygenase-2 and leukotriene B4 dehydrogenase, after that literature survey was done to determine the consistency of traditional uses and molecular docking results with the current knowledge obtained from previous studies and reports. RESULTS AND CONCLUSION: The in-silico study revealed the ability of several chemical constituents, in the plants under investigation, to bind effectively to different targets associated with inflammation, which was consistent with previous reports, indicating that Islamic traditional medicine can be considered as a reliable promising source for developing new anti-inflammatory agents with low toxicity and minimal side effects.
RESUMEN
In an attempt to connect the legacy of centuries of invaluable knowledge from traditional medicine and the current understanding to the molecular mechanism of diseases, we took the advantage of the emergence of in silico screening as a promising tool for identification of potential leads from libraries of natural products. Traditional Chinese Medicine database was subjected to structure based virtual screening for identification of anti-inflammatory compounds using the 3D crystal structure of p38 alpha mitogen activated protein kinase. The molecular docking studies revealed the potential activity of several classes of compounds known to be the constituents of the rhizomes of Alpinia officinarum Hance (Lesser galangal). Five compounds, galangin, kaempferide, isorhamnetin, and two diarylheptanoids, were isolated from the rhizomes of the plant using vacuum liquid chromatography and flash chromatography techniques. The anti-inflammatory activity of these compounds was investigated on HepG2 cells stimulated by lipopolysaccharide. The latter induced the gene expression of proinflammatory cytokines; interleukin-1ß, interleukin-6, tumor necrosis factor alpha. Addition of the 5 isolated compounds downregulated this increased gene expression in a dose dependent manner. Thus, these results indicate that the isolated compounds from A. officinarum could be used as a beneficial source for preventing and treating inflammatory diseases.