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This study focuses on the design and multistep synthesis of diverse structural and functional 3-substituted-2-oxindole derivatives aimed at being dual-active molecules with anti-cancer and anti-inflammatory properties. In vitro evaluations confirmed the dual activity of these derivatives. 4a exhibited GI50 value 3.00E-05 against MDA-MB-231; 4b has shown GI50 value 2E-05 against MDA-MB-231; 4c has shown GI50 value 6E-05 against VERO; and 4d has shown GI50 value 8E-05 each against both MDA-MB-231 and MCF-7. 4e has shown GI50 values 2E-05 and 5E-05 each against both the MCF-7 and VERO. The analysis indicates that compounds 3c (71.19%), 3e (66.84%), and 3g (63.04%) exhibited significant anti-inflammatory activity. Additionally, in silico binding free energy analysis and interaction studies revealed significant correlations between in vitro and computational data, identifying compounds 4d, 4e, 3b, 3i, and 3e as promising candidates. Key residues such as Glu917, Cys919, Lys920, Glu850, Lys838, and Asp1046 were found to play critical roles in ligand binding and kinase inhibition, providing valuable insights for designing potent VEGFR2 inhibitors. The quantum mechanics-based independent gradient model analysis further highlighted the electronic interaction landscape, showing larger attractive peaks and higher electron density gradients for compounds 4d and 4e compared to Sunitinib, suggesting stronger and diverse attractive forces.
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INTRODUCTION: A series of 15 thiazolyl hydrazone derivatives of chromone-3- carbaldehyde have been designed and synthesized by the cyclization of thiosemicarbazone derivatives of chromone-3-carbaldehydes with 4'-substituted-2-bromo acetophenones. METHOD: All these derivatives were evaluated for antioxidant activity by their direct scavenging activity objects to reactive oxygen species such as DPPH, and nitric oxide, as well as in vitro antiinflammatory activity by a protein denaturation method. Most of these synthesized compounds have shown significant antioxidant activity, among which the compounds 5b, 5c, 5e, 5g, and 5j showed very good antioxidant activities in comparison with the standard ascorbic acid. The in vitro anti-inflammatory activity revealed that the compounds 5b, 5g, and 5h possessed significant activity compared to standard diclofenac sodium. RESULT: Additionally, molecular docking studies of these molecules using ovalbumin as the protein showed remarkable interactions with its active site residues, and the results indicated that the binding mode of these compounds closely resembled that of the reference compound, diclofenac sodium. CONCLUSION: Thus, these compounds represent an attractive template for the evaluation of new antiinflammatory and antioxidant agents and might be useful for exploring new therapeutic tools.
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A series of novel substituted 2-pyrimidinyl-2,3-dihydro-1H-naphtho[1,2-e][1, 3]oxazine analogs have been designed and synthesized based on structure-activity relationships from 2-naphthol, substituted pyrimidinyl amines and formalin through ring closure by one-pot three component reaction. These derivatives were evaluated for their in vitro cytotoxicity, cell cycle assay and their inhibitory effect on tubulin polymerization. From the MTT assay, it is clear that most of the synthesized compounds displayed potent cytotoxic activities on HeLa (cervical cancer) and B16F10 (melanoma) cancerous cell lines. The compounds 6b and 6k were found to be more effective against HeLa cell lines and exhibited significant cytotoxicity (with IC50 values 1.26 ± 0.12 µM and 1.16 ± 0.27 µM respectively), accumulation of HeLa cells in G2/M phase and exhibiting induced apoptosis. The immunohistochemistry and fluorescence assays showed that these compounds 6b and 6k inhibited the microtubule assembly in human cervical cancer cells (HeLa) at 2 µM concentration. Furthermore, molecular docking studies of these molecules revealed their better-fit potential as anticancer molecules and have a high affinity for colchicine binding site, indicating more inhibitory potential at the cellular level. Our studies suggest that the newly synthesized compounds may become promising leads for the development of new anti-cancer agents.Communicated by Ramaswamy H. Sarma.
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BACKGROUND: Recently, researchers have worked on the development of new methods for the synthesis of bioactive heterocycles using polyethylene glycol as a green solvent. In this context, we report the synthesized 2-(2-hydrazinyl) thiazoles for their in vitro antioxidant, in vitro anti-inflammatory and in vitro anti-cancer activities. OBJECTIVE: The objective of the study was to develop novel antioxidant, anti-inflammatory and anti-cancer drugs. METHODS: At the outset, the condensation of substituted acetophenones 1, thiosemicarbazide 2, and α-haloketones 3 was carried out using PEG-400 (20 mL) in the presence of 5 mol% glacial acetic acid to afford thiosemicarbazones intermediate. Furthermore, these thiosemicarbazones were reacted with α-haloketones 3 to obtain appropriate 2-(2-hydrazinyl) thiazoles. The synthesized compounds were in vitro tested for their antioxidant, anti-inflammatory, and anti-cancer activity. RESULTS: In vitro evaluation report showed that nearly all molecules possessed potential antioxidant activity against 2,2-Diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO), superoxide radical (SOR) and hydrogen peroxide (H2O2) radical scavenging activity. Most 2-(2-hydrazinyl) thiazoles derivatives have shown potential anti-inflammatory activity as compared to diclofenac sodium as a reference standard. 2-(2-Hydrazinyl) thiazoles derivatives showed significant anticancer activity for human leukemia cell line K-562 compared to adriamycin as a reference standard. CONCLUSION: All tested compounds showed potential 2,2-Diphenyl-1-picrylhydrazyl (DPPH) and nitric oxide (NO) radical scavenging activity. Among the tested series, 4b, 4d and 4e exhibited good hydrogen peroxide and 4b, 4e, 4f and 4g showed excellent superoxide radical scavenging activity. In addition, the 4b, 4e and 4g compounds revealed potent in vitro anti-inflammatory activity against standard diclofenac sodium drug. 2-(2-Hydrazinyl) thiazole derivatives, such as 4c and 4d, showed significant anticancer activity against human leukemia cell line K-562. Thus, these molecules provide an interesting template for the design and development of new antioxidant, anti-inflammatory, and anti-cancer agents.
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Antineoplásicos , Tiossemicarbazonas , Humanos , Antioxidantes/farmacologia , Simulação de Acoplamento Molecular , Tiazóis , Peróxido de Hidrogênio/farmacologia , Óxido Nítrico/química , Diclofenaco , Superóxidos , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologiaRESUMO
BACKGROUND: A literature survey revealed that many imidazo-thiadiazole molecules were used as key intermediates for the development of novel drugs. The synthesized imidazo-thiadiazole derivatives were tested for their in vitro antioxidant and anti-inflammatory properties. The purpose of this research paper is to provide readers with information regarding diseases caused by free radicals. OBJECTIVE: The objective of this study is to develop novel antioxidant and anti-inflammatory drugs. METHODS: Imidazo-thiadiazole derivatives 5a-f were synthesized through cyclo-condensation reactions in two steps. First, the synthesis of 2-amino-thiadiazole derivatives from substituted aromatic carboxylic acids and thiosemicarbazide by using POCl3 as a solvent as well as a catalyst was performed. In the next step, imidazo-thiadiazoles were prepared from 2-amino-thiadiazole derivatives with appropriate α-haloketones in the presence of polyethylene glycol-300 (PEG-300) as a green solvent. These imidazo- thiadiazole derivatives were prepared by using a novel method. The synthesized compounds were in vitro tested for their antioxidant and anti-inflammatory activities. RESULTS: In vitro evaluation report showed that nearly all molecules possess potential antioxidant activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO), superoxide radical (SOR), and hydrogen peroxide (H2O2) radical scavenging activity. Most of the imidazo-thiadiazole derivatives have shown significant anti-inflammatory activity as compared to diclofenac sodium as a reference standard. CONCLUSION: In the search for novel therapies to treat inflammation and oxidation, we have made efforts to develop anti-inflammatory and antioxidant agents with a preeminent activity. Imidazo-thiadiazoles 5a, 5e as well as 5f showed potential anti-inflammatory activity. All tested imidazo-thiadiazole deriv-atives (5a-f) showed potential antioxidant activity against one more radical scavenging species as com-pared to ascorbic acid as the reference standard. Thus, imidazo-thiadiazole derivatives constitute an interesting template for the design and development of new antioxidant as well as anti-inflammatory agents.
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Tiadiazóis , Tiadiazóis/farmacologia , Antioxidantes/farmacologia , Peróxido de Hidrogênio , Anti-Inflamatórios/farmacologia , Ácido AscórbicoRESUMO
Aptamers are small, functional single-stranded DNA or RNA oligonucleotides that bind to their targets with high affinity and specificity. Experimentally, aptamers are selected by the systematic evolution of ligands by exponential enrichment (SELEX) method. Here, we have used rational drug designing and bioinformatics methods to design the aptamers, which involves three different steps. First, finding a probable aptamer-binding site, and second, designing the recognition and structural parts of the aptamers by generating a virtual library of sequences, selection of specific sequence via molecular docking, molecular dynamics (MD) simulation, binding energy calculations, and finally evaluating the experimental affinity. Following this strategy, a 16-mer DNA aptamer was designed for Annexin A1 (ANXA1). In a direct binding assay, DNA1 aptamer bound to the ANXA1 with dissociation constants value of 83 nM. Flow cytometry and fluorescence microscopy results also showed that DNA1 aptamer binds specifically to A549, HepG2, U-87 MG cancer cells that overexpress ANXA1 protein, but not to MCF7 and L-02, which are ANXA1 negative cells. We further developed a novel system by conjugating DNA1 aptamer with doxorubicin and its efficacy was studied by cellular uptake and cell viability assay. Also, anti-tumor analysis showed that conjugation of doxorubicin with aptamer significantly enhances targeted therapy against tumors while minimizing overall adverse effects on mice health.
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Surgery is considered to be the favored approach for the treatment of most solid tumor malignancies. The quality of life among cancer patients has significantly improved due to advancements in instrumentation and surgical techniques; however, the recurrence of tumors and metastasis after operation remains challenging and results in a decreased quality of life and an increase in the mortality rate. Therefore, there is a need to explore applicable approaches to eradicate the circulating tumor cells and any residual tumor at the surgical site to inhibit the recurrence of the tumor and reduce the threat of distant metastasis. Recently drug delivery systems have been used to deliver immunotherapy or chemotherapy agents, which could augment the efficacy of surgical resection. In this review, we have summarized the efficacy and the recent progress of controlled drug delivery systems based approaches for post-surgical cancer treatment. Clinical translation challenges and opportunities have also been discussed.
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Antineoplásicos/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Neoplasias/tratamento farmacológico , Animais , Humanos , Hidrogéis/química , Micelas , Nanofibras/químicaRESUMO
By understanding the rampant infections of Mycobacterium tuberculosis (Mtb) and inflammations caused due to the generation of radical species during the Mtb infection, a series of (E)-2-(2-allylidenehydrazinyl)thiazole derivatives, with dual-action properties, was designed. The molecules were designed with a considerable variation in LogP, one of the critical parameters in physicochemical properties, and analyzed for their drug-likeness. For the synthesis, a simple, green, and multicomponent one-pot synthesis method was developed. The in vitro inhibition potentials were evaluated against Mtb H37 Rv by the microplate Alamar Blue assay. The results reveal that compound 6 was potent, with a MIC value of 6.5 µg/ml, and showed better interactions with the KasA protein with binding free energy (ΔG) of -9.4 kcal/mol. Also, the radical scavenging properties were studied to establish the dual-action properties of the molecules. Compound 9 exhibited promising antioxidant and nitric oxide radical scavenging activities, with 81.7% and 81.0%, respectively, at 1,000-µg/ml concentration.
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Antituberculosos/farmacologia , Desenho de Fármacos , Sequestradores de Radicais Livres/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tiazóis/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Relação Dose-Resposta a Droga , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/química , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/químicaRESUMO
The efficient metal-free oxidative coupling of arylmethylamines with indoles has been developed using molecular oxygen as a green oxidant. The present reaction provides a novel route towards the synthesis of 3,3'-bis(indolyl)methanes in excellent yields of up to 95% via C-C and C-N bond formation. This attractive and environmentally friendly one-pot protocol is a simple procedure that features inexpensive acetic acid as the catalyst and molecular oxygen as the sole oxidant, and it supports a wide substrate scope with the good tolerance of functional groups.
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BACKGROUND: Cancer is one of the leading diseases responsible for deaths in the society. According to the American cancer society, there will be 95,270 new cases of colon cancer in the U.S. in 2016. When a normal cell turns cancerous they develop into tumours, which produce various pro-inflammatory and inflammatory cytokines and chemokines that attract leukocytes to the site of growth. The main aim of this paper is to introduce readers about the increased number of cancer patient, effects of cancer and need of research on same. METHODS: The target molecules were prepared by reacting pyrazolealdehyde with appropriate aromatic ketone by using polyethylene glycol (PEG-300) as green solvent and catalyst to yield chalcone. Furthermore, the reaction of chalcones with thiosemicabazide yields asymmetric 1-thiocarbamoyl pyrazoles. All the newly synthesized compounds were in vitro screened for their anticancer activities against Colon SW-620 by employing the sulforhodamine B (SRB) assay method. Also all the synthesized compounds tested for in vitro antioxidant and anti-inflammatory activity by using known literature methods. RESULTS: Preliminary in vitro evaluation indicated that most of the compounds 4c, 4d and 4e possess distinct cytotoxicity profile against Colon SW-620 cell line compared to standard drug adriamycin. All the tested compounds showed good to excellent antioxidant activity against one or more reactive (H2O2, DPPH, SOR and NO) radical scavenging species. Additionally, all the synthesized compounds were screened for their in vitro antiinflammatory activity. Compounds 4a, 4b and 4e shows potent anti-inflammatory activity as compared to diclofenac sodium as a standard reference. CONCLUSION: New anti- Colon SW-620 cancer agents are the need of time, we trust that 1-thiocarbamoyl pyrazole derivatives 4c, 4d and 4e constitute an interesting template for the evaluation of new anticancer agent also antioxidant and anti-inflammatory work may provide an interesting insight for further development.
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Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Neoplasias do Colo/patologia , Pirazóis/síntese química , Pirazóis/farmacologia , Tiocarbamatos/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Polietilenoglicóis/química , Pirazóis/químicaRESUMO
1,3-oxazine nucleus and thiazolyl group features prominently in many biologically important natural products as well as bioactive molecules. A series of novel 2-thiazolyl substituted-2,3-dihydro-1H-naphtho [1,2-e][1,3]oxazine derivatives were designed and synthesized based on their structure-activity relationships (SARs) from 2-naphthol, substituted thiazolyl amines and formalin through ring closure by one-pot three component reaction. These derivatives were first evaluated for their inhibitory effect on HIV-1 Reverse Transcriptase (RT) enzyme activity. Out of 14 compounds, 4 showed potent inhibition of HIV-1 RT activity at significantly low concentration. Docking studies of these molecules revealed their high affinity binding to several amino acids of HIV-1 RT which are less sensitive to point mutations. Furthermore, anti-HIV activity of these molecules was analysed in a CD4+ T cell-line, which indicates that Therapeutic Index (TI) of some of these compounds is better than Zidovudine and Efavirenz, known HIV-1 RT inhibitors. Taken together, our studies report for the first time some novel naphthoxazine derivatives with significant TI, which is through inhibition of HIV-1 RT activity.
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Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Naftalenos/farmacologia , Oxazinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Tiazóis/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Transcriptase Reversa do HIV/metabolismo , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/química , Oxazinas/síntese química , Oxazinas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/químicaRESUMO
The new series of asymmetrical pyrazole curcumin analogues 4a-g were synthesized by using polyethylene glycol (PEG-400) as a green reaction medium and evaluated for their in vivo analgesic and in vitro antioxidant (H2 O2 , DPPH, Ferrous reducing power and Nitric oxide scavenging activity) and anti-inflammatory activities. All the compounds synthesized 4a-g showed the potential to demonstrate analgesic activity as compared to the standard ibuprofen. Among the tested series, compounds 4e and 4b exhibited good hydrogen peroxide scavenging activity as compared to the standard butylated hydroxy toluene (BHT). Compounds 4b, 4d, 4f, and 4g showed good DPPH free radical scavenging activity. Compounds 4b, 4c, 4d, 4e and 4g showed excellent ferrous-reducing power activity, whereas all the compounds showed better nitric oxide scavenging activity than standard ascorbic acid. Additionally, all the synthesized compounds were also screened for their in vitro anti-inflammatory activity. Compounds 4b, 4d, 4f and 4g showed good anti-inflammatory activity as compared to standard diclofenac sodium.
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Anti-Inflamatórios/síntese química , Curcumina/análogos & derivados , Curcumina/farmacologia , Polietilenoglicóis/química , Pirazóis/química , Administração Oral , Analgésicos/síntese química , Analgésicos/metabolismo , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Espectroscopia de Ressonância Magnética , Camundongos , Óxido Nítrico/química , Desnaturação Proteica , Espectrofotometria InfravermelhoRESUMO
A new series of fluoro substituted pyrazoline derivatives 5a-g and 6a-g were synthesized in good to excellent yield from the corresponding pyrazole chalcones, 4a-g, by using polyethylene glycol-400 (PEG-400) as an alternative reaction medium. The newly synthesized compounds were characterized and screened for their in vivo antiinflammatory and analgesic activity. Compounds 5g and 6g were found to be more potent than standard drug Diclofenac and six other compounds 5b, 5c, 5f, 6b, 6c and 6f showed significant antiinflammatory activity as compared to standard drug. Compounds 5c, 5d, 5e, 5f, 6c, 6d, 6e and 6f showed significant analgesic activity as compared to standard drug Aspirin.
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Analgésicos/síntese química , Anti-Inflamatórios/síntese química , Flúor/química , Polietilenoglicóis/química , Pirazóis/química , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Edema/induzido quimicamente , Edema/tratamento farmacológico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Cauda/efeitos dos fármacosRESUMO
A simple and convenient route is described for the synthesis of novel hetero 1,3-diaryl-2-propen-1-ones (chalcones) by using recyclable PEG-400 as an alternative reaction solvent. The reaction is clean with excellent yield, shorter reaction time and reduces the use of volatile organic compounds (VOCs). All the synthesized compounds were evaluated for their antimicrobial activities against several pathogenic representatives.