RESUMEN
In this paper, we have reported seventeen novel synthetic organic compounds derived from marine bromopyrrole alkaloids, exhibiting potential inhibition of biofilm produced by Gram-positive bacteria. Compound 5f with minimumbiofilm inhibitory concentration(MBIC) of 0.39, 0.78 and 3.125 µg/mL against MSSA, MRSA and SE respectively, emerged as promising anti-biofilm lead compounds. In addition, compounds 5b, 5c, 5d, 5e, 5f, 5h, 5i and 5j revealed equal potency as that of the standard drug Vancomycin (MBIC = 3.125 µg/mL) against Streptococcus epidermidis. Notably, most of the synthesized compounds displayed better potency than Vancomycin indicating their potential as inhibitors of bacterial biofilm. The cell viability assay for the most active hybrid confirms its anti-virulence properties which need to be further researched.
Asunto(s)
Alcaloides/química , Antibacterianos/síntesis química , Bacterias Grampositivas/fisiología , Alcaloides/síntesis química , Alcaloides/farmacología , Animales , Antibacterianos/química , Antibacterianos/farmacología , Organismos Acuáticos/química , Organismos Acuáticos/metabolismo , Biopelículas/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Bacterias Grampositivas/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Percepción de Quorum/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/fisiología , Streptococcus/efectos de los fármacos , Relación Estructura-Actividad , Células VeroRESUMEN
The natural stilbenoids combretastatin A-4 (CA4) and combretastatin A-1 (CA1) are potent antitubulin agents demonstrating antimitotic activity as well as tumor vascular disruption property. Due to structural simplicity and potent cytotoxicity of CA4 and CA1, they are considered as promising leads for the development of potent anticancer agents. In fact, scientific fraternity is motivated to synthesize several derivatives of CA4 and CA1 as novel therapeutic agents. In the literature, several studies have been carried out to evaluate the medicinal chemistry, pharmacology and structure-activity relationships (SAR) of a variety of modified combretastatin derivatives. The present report aimed at comprehensively revising the recent advancements (2006-2014) in the medicinal chemistry and SAR of diversified combretastatin analogues. The published data concerning new combretastatin A-4 analogues as antimitotic anticancer agents are presented and SAR is reviewed and discussed.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/aislamiento & purificación , Bibencilos/química , Productos Biológicos/química , Descubrimiento de Drogas/tendencias , Animales , Antimitóticos/química , Antimitóticos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Descubrimiento de Drogas/métodos , Humanos , Relación Estructura-ActividadRESUMEN
In the past decades, tricyclic acridone ring system has become one of the major research interests of the medicinal chemists due to the biological significance of this moiety in drug design and drug discovery. Acridone scaffold has substantial bio-potential since it possess crucial activities such as antibacterial, antimalarial, antiviral and anti-neoplastic. The diverse biological activity of acridone and its prospective in reversal of multi-drug resistance has attracted attention of medicinal chemists to explore this scaffold especially to treat multi-drug resistance in cancer. Considering this potential in this review we have summarized the synthesis and the antitumor activities of different acridone derived compounds reported from 2000 to 2014.
Asunto(s)
Acridinas/química , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Diseño de Fármacos , Acridonas , Animales , Antineoplásicos/síntesis química , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales/tendencias , Humanos , Neoplasias/tratamiento farmacológicoRESUMEN
Synthesis of novel set of forty semicarbazide/thiosemicarbazide hybrids inspired from marine bromopyrrole alkaloids is reported. Biological screening of these hybrids against a panel of five human cancer cell lines identified a number of hits endowed with interesting cytotoxicity profile. Compounds 5c and 5e (IC50 = 0.03 µm), 5t (IC50 = 0.03 µm), 4s (IC50 = 0.07 µm), and 5n (IC50 = 0.01 µm) displayed maximum cytotoxicity toward hormone-dependent breast cancer cells MCF7, hepatic cancer cells WRL68, colon cancer cells CaCO2 and mouth and oral cancer cells KB403, respectively. The most active hits were further investigated for their potential to inhibit MMP-2 and MMP-12. Compound 5e showed maximum activity (IC50 = 1.8 µm) toward MMP-2. Further, we preformed anti-invasive assay on the most active compounds, where CaCO2 tumor cell migration was significantly decreased (77.9%) by hybrid 5e. The non-toxicity toward human VERO cells (IC50 = 83.1 to 231.8 µm) indicated the selectivity of most active hits (5c, 5e, 5t and 5n) toward cancer cells.
Asunto(s)
Alcaloides/síntesis química , Alcaloides/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Inhibidores de la Metaloproteinasa de la Matriz/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Alcaloides/química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Células CACO-2 , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células MCF-7 , Metaloproteinasa 12 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz/química , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Neoplasias/patología , Pirroles/química , Semicarbacidas/síntesis química , Semicarbacidas/química , Semicarbacidas/farmacología , Relación Estructura-ActividadRESUMEN
In search of novel cytotoxic agents based on acridone scaffold, twenty five derivatives of acridone-2- carboxamide were synthesized and evaluated against a panel of eleven cancer cell lines by using MTT assay. Amides, A5 and A8 (IC50 = 0.3 µM) exhibited good cytotoxicity against MCF7. Compound A22 (IC50 = 4.3 µM) was found to be selectively cytotoxic against cancer cell line MCF7 and KB403. Particularly, promising cytotoxic activities were shown by amides A6 (IC50 = 0.7 µM), A16 (IC50 = 6.3 µM), A8 (IC50 = 0.9 µM ), A21 (IC50 = 1.3 µM), A5 (IC50 = 2.9 µM), A8 (IC50 = 2.8 µM), A14 (IC50 = 0.8 µM), A9 (IC50 = 0.8 µM) and A8 (IC50 = 0.4 µM) against cell lines; PA1, WRL68, CaCO2, TK-10, K-562, PC-3, HOP-92, ECV-304 and UACC-257, respectively. The favorable cytotoxic profile and non-toxicity towards normal human cells displayed by the derivative revealed their potential for further anticancer drug developments.
Asunto(s)
Acridinas/química , Amidas/síntesis química , Amidas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Acridonas , Amidas/química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Neoplasias/patología , Relación Estructura-ActividadRESUMEN
Azetidin-2-one, a ß -lactam four-membered heterocyclic ring is widely identified for its diverse medicinal properties. Ezetimibe a cholesterol absorption inhibitor and Aztreonam a potent cephalosporinase inhibitor proved the medicinal value of azetidin-2-ones. On the other hand marine bromopyrrole alkaloids are well known for their diverse biological significance. Hence twenty novel conjugates of azetidin-2-ones integrated with 4,5-dibromopyrrole motif were synthesized and screened for antineoplastic activity using MTT assay. Synthesized hybrids displayed good antineoplastic profile particularly towards breast cancer cell line MCF7, where hybrid 5e displayed maximum cytotoxicity (IC50 = 0.5 µM). The selective cytotoxicity displayed by these conjugates towards tested cancer cells with non-toxicity against normal human VERO cells indicated their potential for further antineoplastic drug development.
Asunto(s)
Alcaloides/farmacología , Antineoplásicos/farmacología , Diseño de Fármacos , Hidrocarburos Bromados/farmacología , Pirroles/farmacología , Alcaloides/síntesis química , Alcaloides/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Hidrocarburos Bromados/síntesis química , Hidrocarburos Bromados/química , Células MCF-7 , Estructura Molecular , Pirroles/síntesis química , Pirroles/química , Relación Estructura-ActividadRESUMEN
We report the synthesis and screening of forty novel 4-nitropyrrole-semicarbazide conjugates inspired from the reported bio-potential of bromopyrrole alkaloids and semicarbazide derivatives for antimicrobial activity. Herein, hybrids 5k-5o, 5r, 5s and 5t displayed four-fold increased activity (MIC=0.39 µg/mL) against Escherichia coli compared to standard ciprofloxacin. Eight hybrids, 5k-5o and 5r-5t displayed equal antibacterial activity (MIC=1.56 µg/mL) against Klebsiella pneumonia compared to standard ciprofloxacin. Hybrid, 5k-5o (MIC=0.195 µg/mL) displayed highly potent antibacterial activity against MSSA as compared to standard ciprofloxacin. Eight-fold superior activity was observed for four hybrids 5k-5m and 5o (MIC=0.39 µg/mL) against MRSA. Further, nine hybrids displayed four-fold superior antifungal activity (MIC=0.78 µg/mL) compared to standard Amphotericin B. Encouraging MICs of these hybrids recognize them as promising leads for development of potential antimicrobial drugs.