Synthesis, Antimalarial, Antileishmanial, and Cytotoxicity Activities and Preliminary In Silico ADMET Studies of 2-(7-Chloroquinolin-4-ylamino)ethyl Benzoate Derivatives.

A series of heterocyclic chloroquine hybrids, containing a chain of two carbon atoms at position four of the quinolinic chain and acting as a link between quinoline and several benzoyl groups, is synthesized and screened in vitro as an inhibitor of ß-hematin formation and in vivo for its antimalarial activity against chloroquine-sensitive strains of Plasmodium berghei ANKA in this study. The compounds significantly reduced haeme crystallization, with IC50 values < 10 µM. The values were comparable to chloroquine's, with an IC50 of 1.50 ± 0.01 µM. The compounds 4c and 4e prolonged the average survival time of the infected mice to 16.7 ± 2.16 and 14.4 ± 1.20 days, respectively. We also studied the effect of the compounds 4b, 4c, and 4e on another important human parasite, Leishmania mexicana, which is responsible for cutaneous leishmaniasis, demonstrating a potential leishmanicidal effect against promasigotes, with an IC50 < 10 µM. Concerning the possible mechanism of action of these compounds on Lesihmania mexicana, we performed experiments demonstrating that these three compounds could induce the collapse of the parasite mitochondrial electrochemical membrane potential (Δφ). The in vitro cytotoxicity assays against mammalian cancerous and noncancerous human cell lines showed that the studied compounds exhibit low cytotoxic effects. The ADME/Tox analysis predicted moderate lipophilicity values, low unbound fraction values, and a poor distribution for these compounds. Therefore, moderate bioavailability was expected. We calculated other molecular descriptors, such as the topological polar surface area, according to Veber's rules, and except for 2 and 4i, the rest of the compounds violated this descriptor, demonstrating the low antimalarial activity of our compounds in vivo.

Síntesis y actividad antiproliferativa de una mezcla de derivados de (+/_) 7-clo-ro-(4-tioalquilquinolina). Inducción de apoptosis y daño sobre el ADn/aRN

Después de las enfermedades cardiovasculares, el cáncer, una patología no transmisible, ha sido considerado como la segunda causa de muertes cada año a nivel global y como la barrera más importante para aumentar la esperanza de vida en el siglo 21. Se han alcanzado avances de gran relevancia en su prevención y tratamiento; sin embargo, existe aún un largo camino por recorrer para alcanzar un tratamiento efectivo para cada tipo de cáncer. En este trabajo se describen enfoques de reposicionamiento y síntesis de moléculas híbridas con potencial actividad antineoplásica. Para obtener el al-dehído intermediario clave, se empleó la metodología de oxidación de Dess-Martin, que fue acoplado con las cetonas correspondientes usando LDA; se generó así una mezcla racémica para cada uno de los compuestos híbridos propuestos. La actividad antiproliferativa in vitro de los compuestos finales se evaluó frente a ocho líneas celulares derivadas de tumores sólidos humanos, y cuatro líneas celulares no cancerosas. El compuesto 11d resulto ser el más efectivo y con mayor índice de seguridad. Los resultados sugirieron que estos compuestos podrían bloquear el ciclo celular e inducir la apop-tosis y la muerte en las células CCRF-CEM de forma dependiente de la dosis in vitro.

After cardiovascular diseases, cancer, a non-communicable pathology, has been considered the second cause of death each year globally and as the most important barrier to increasing life expectancy in the 21st century. Advances of great relevance have been made in its prevention and treatment, however, there is still a long way to go to achieve an effective treatment for each type of cancer. This paper describes approaches to reposition and synthesis of hybrid molecules with potential antineoplastic activity. To obtain the key intermediate aldehyde, the Dess-Martin oxidation methodology was used, which was coupled with the corresponding ketones using LDA. The final hybrid compounds were obtained as a racemic mixture. The in vitro antiproli-ferative activity of the final compounds was evaluated against eight cell lines derived from human solid tumors, and four non-cancerous cell lines. The compound 11d turned out to be the most effective and with the highest safety index. The results suggested that these compounds could block the cell cycle and induce apoptosis and death in CCRF-CEM cells in a dose-dependent manner in vitro.

Depois das doenças cardiovasculares, o câncer, uma patologia não transmissível, tem sido considerado como a segunda causa de mortes a cada ano em todo o mundo e como a barreira mais importante para o aumento da expectativa de vida no século 21. Avanços de grande relevância têm sido feitos na sua prevenção e tratamento, no entanto, ainda há um longo caminho a percorrer para alcançar um tratamento eficaz para cada tipo de câncer. Este artigo descreve abordagens para o reposicionamento e síntese de moléculas híbridas com potencial atividade antineoplásica. Para a obtenção do aldeído intermediário chave, foi utilizada a metodologia de oxidação de Dess-Martin, que foi acoplada com as cetonas correspondentes usando LDA. Os compostos híbridos finais foram obtidos como uma mistura racêmica. A atividade antiproliferativa in vitro dos compostos finais foi avaliada contra oito linhagens celulares derivadas de tumores sólidos humanos e quatro linhagens celulares não cancerosas. O composto 11d revelou-se o mais eficaz e com o maior índice de segurança. Os resultados sugeriram que estes compostos poderiam bloquear o ciclo celular e induzir apoptose e morte em células CCRF-CEM de forma dose-de-pendente in vitro.

Efecto del compuesto N-2,6-dicloro-aralquil-2-Aminoindano en la conducta estereotipada de ratas. Acción dopaminérgica selectiva central sobre los ganglios basales más que en las estructuras límbicas / Effect of the compound N-2,6-dichloro-aralkyl-2-aminoindane on the stereotyped behavior of rats. Selective action on the central dopaminergic system in the basal ganglia over limbic structures

Resumen La dopamina 1, está implicada en trastornos neurodegenerativos que afectan al sistema nervioso central (SNC) tales como la enfermedad de Parkinson, entre otros. Aunque no se dispone aún de ningún fármaco capaz de prevenir, detener o curar la progresión de estas enfermedades, son numerosos los compuestos que han sido diseñados, sintetizados y evaluados farmacológicamente, que han aportado las generalizaciones farmacofóricas del receptor dopaminérgico, necesarias para la búsqueda de un fármaco capaz de mejorar o curar estas patologías. Los derivados 2-aminoindano-N-aralquílicos han mostrado tener actividad selectiva en el sistema dopaminérgico central, de modo tal que los compuestos clorhidratos de N-[(2,4-diclorofenil)-1-metil- etil]-2-aminoindano 2 y N-[(3,4-diclorofenil)-1-metil-etil]-2-aminoindano 3 demostraron tener actividad agonística mediada por mecanismos dopaminérgicos centrales. Con el propósito de contribuir en la búsqueda de nuevos fármacos que permitan restablecer la homeostasis de la transmisión dopaminérgica en la enfermedad de Parkinson, el compuesto N-2,6-dicloro-aralquil-2-aminoindano 4 fue diseñado a través de estrategias de la química medicinal, que contienen las aproximaciones farmacofóricas de los profármacos. La evaluación farmacológica del compuesto 4, en la conducta estereotipada en ratas macho de la cepa Sprague Dawley, demostró tener actividad agonística a través de la activación de los mecanismos dopaminérgicos centrales y mostró mayor selectividad en las respuestas de conductas estereotipadas propias de los ganglios basales sobre las respuestas conductuales propias de las estructuras límbicas.

Abstract Dopamine 1 is involved in neurodegenerative disorders affecting the central nervous system (CNS), such as Parkinson's disease. Despite the absence of some available drugs capable of preventing, stopping or curing the progression of such diseases, there are numerous compounds designed, synthesized, and pharmacologically tested which give rise to pharmacophoric generalizations about the dopaminergic receptor required for the search of a drug able to improve or cure those pathologies. N-aralkyl-2-aminoindane derivatives have shown selective activity in the central dopaminergic system. Both the N-[(2,4-dichlorophenyl)-1-methyl-ethyl]-2-aminoindane hydrochloride 2 and N-[(3,4-dichlorophenyl)-1-methyl-ethyl]-2-aminoindane hydrochloride 3 showed an agonistic activity mediated by central dopaminergic mechanisms. To contribute to the search of new drugs able to re-establish homeostasis in the dopaminergic transmission in Parkinson's disease, the compound N-2,6- dichloro-aralkyl-2-aminoindane 4 was designed through medicinal chemistry strategies that contain pharmacophoric approximations of prodrugs. The pharmacological evaluation of compound 4 in the stereotyped behavior of male Sprague Dawley rats showed agonistic activity through the activation of central dopaminergic mechanisms and a higher selectivity in the responses of stereo- typed behavior characteristic of the basal ganglia over the typical responses from limbic structures.

Molecular Mechanisms of Chloroquine and Hydroxychloroquine Used in Cancer Therapy.

Tumour relapse, chemotherapy resistance, and metastasis continue to be unsolved issues in cancer therapy. A recent approach has been to scrutinise drugs used in the clinic for other illnesses and modify their structure to increase selectivity to cancer cells. Chloroquine (CQ) and hydroxychloroquine (HCQ), known antimalarials, have successfully treated autoimmune and neoplastic diseases. CQ and HCQ, well-known lysosomotropic agents, induce apoptosis, downregulate autophagy, and modify the tumour microenvironment. Moreover, they affect the Toll 9/NF-κB receptor pathway, activate stress response pathways, enhance p53 activity and CXCR4-CXCL12 expression in cancer cells, which would help explain their effects in cancer treatment. These compounds can normalise the tumourassociated vasculature, promote the activation of the immune system, change the phenotype of tumour-associated macrophages (from M2 to M1), and stimulate cancer-associated fibroblasts. We aim to review the historical aspects of CQ and its derivatives and the most relevant mechanisms that support the therapeutic use of CQ and HCQ for the treatment of cancer.

Novel 7-Chloro-(4-thioalkylquinoline) Derivatives: Synthesis and Antiproliferative Activity through Inducing Apoptosis and DNA/RNA Damage.

A series of 78 synthetic 7-chloro-(4-thioalkylquinoline) derivatives were investigated for cytotoxic activity against eight human cancer as well as 4 non-tumor cell lines. The results showed, with some exceptions, that sulfanyl 5-40 and sulfinyl 41-62 derivatives exhibited lower cytotoxicity for cancer cell lines than those of well-described sulfonyl N-oxide derivatives 63-82. As for compound 81, the most pronounced selectivity (compared against BJ and MRC-5 cells) was observed for human cancer cells from HCT116 (human colorectal cancer with wild-type p53) and HCT116p53-/- (human colorectal cancer with deleted p53), as well as leukemia cell lines (CCRF-CEM, CEM-DNR, K562, and K562-TAX), lung (A549), and osteosarcoma cells (U2OS). A good selectivity was also detected for compounds 73 and 74 for leukemic and colorectal (with and without p53 deletion) cancer cells (compared to MRC-5). At higher concentrations (5 × IC50) against the CCRF-CEM cancer cell line, we observe the accumulation of the cells in the G0/G1 cell phase, inhibition of DNA and RNA synthesis, and induction of apoptosis. In addition, X-ray data for compound 15 is being reported. These results provide useful scientific data for the development of 4-thioalkylquinoline derivatives as a new class of anticancer candidates.

Synthesis, Leishmanicidal, Trypanocidal, Antiproliferative Assay and Apoptotic Induction of (2-Phenoxypyridin-3-yl)naphthalene-1(2H)-one Derivatives.

The coexistence of leishmaniasis, Chagas disease, and neoplasia in endemic areas has been extensively documented. The use of common drugs in the treatment of these pathologies invites us to search for new molecules with these characteristics. In this research, we report 16 synthetic chalcone derivatives that were investigated for leishmanicidal and trypanocidal activities as well as for antiproliferative potential on eight human cancers and two nontumor cell lines. The final compounds 8−23 were obtained using the classical base-catalyzed Claisen−Schmidt condensation. The most potent compounds as parasiticidal were found to be 22 and 23, while compounds 18 and 22 showed the best antiproliferative activity and therapeutic index against CCRF-CEM, K562, A549, and U2OS cancer cell lines and non-toxic VERO, BMDM, MRC-5, and BJ cells. In the case of K562 and the corresponding drug-resistant K562-TAX cell lines, the antiproliferative activity has shown a more significant difference for compound 19 having 10.3 times higher activity against the K562-TAX than K562 cell line. Flow cytometry analysis using K562 and A549 cell lines cultured with compounds 18 and 22 confirmed the induction of apoptosis in treated cells after 24 h. Based on the structural analysis, these chalcones represent new compounds potentially useful for Leishmania, Trypanosoma cruzi, and some cancer treatments.

One-Pot Multicomponent Synthesis of Methoxybenzo[h]quinoline-3-carbonitrile Derivatives; Anti-Chagas, X-ray, and In Silico ADME/Tox Profiling Studies.

Several methoxybenzo[h]quinoline-3-carbonitrile analogs were designed and synthesized in a repositioning approach to developing compounds with anti-prostate cancer and anti-Chagas disease properties. The compounds were synthesized through a sequential multicomponent reaction of aromatic aldehydes, malononitrile, and 1-tetralone in the presence of ammonium acetate and acetic acid (catalytic). The effect of the one-pot method on the generation of the target product has been studied. The compounds were in vitro screened against bloodstream trypomastigotes of T. cruzi (NINOA and INC-5 strains) and were most effective at showing a better activity profile than nifurtimox and benznidazole (reference drugs). A study in silico on absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) profiling to help describe the molecular properties related to the pharmacokinetic aspects in the human body of these compounds was reported. In addition, X-ray data for the compound 2-Amino-5,6-dihydro-4-(3-hydroxy-4-methoxy-phenyl)-8-methoxybenzo[h]quinoline-3-carbonitrile 6 was being reported. Spectral (IR, NMR, and elemental analyses) data on all final compounds were consistent with the proposed structures.

Synthesis of 5H-indeno[1,2-b]pyridine derivatives: Antiproliferative and antimetastatic activities against two human prostate cancer cell lines.

This study describes the direct synthesis of 2-amino-4-(phenylsubstituted)-5H-indeno[1,2-b]pyridine-3-carbonitrile derivatives 5-21, through sequential multicomponent reaction of aromatic aldehydes, malononitrile, and 1-indanone in the presence of ammonium acetate and acetic acid (catalytic). The biological study showed that compound 10 significantly impeded proliferation of the cell lines PC-3, LNCaP, and MatLyLu. The antimetastatic effects of compound 10 could be related with inhibition of MMP9 in the PC-3 and LNCaP human cell lines. On the basis of a study of the structure-activity relationship of these compounds, we propose that the presence of two methoxy groups at positions 6 and 7 of the indeno nucleus and a 4-hydroxy-3-methoxy phenyl substitution pattern at position 4 of the pyridine ring is decisive for these types of molecules to exert very good antiproliferative and antimetastatic activities.

Synthesis and antimalarial and anticancer evaluation of 7-chlorquinoline-4-thiazoleacetic derivatives containing aryl hydrazide moieties.

Twelve 7-chloroquinoline derivatives were designed and synthesized using the principle of molecular hybridization through the coupling of 2-[2-(7-chloroquinolin-4-ylthio)-4-methylthiazol-5-yl]acetic acid 1 with various benzoyl hydrazines 2a-l. The synthetic compounds were tested as antimalarials. Some of them showed an efficient in vitro activity as inhibitors of ß-hematin formation and an in vivo activity in a murine model, resulting in compounds 8 and 9 as the most active ones with IC50 values of 0.65 ± 0.09 and 0.64 ± 0.16 µM, respectively. The effects of the compounds on the cell viability, cell cycle, and apoptosis induction of A549 and MCF-7 cancer cell lines were also examined. Our data showed that compounds 6 and 12 were the most active agents, decreasing the cell viability of MCF-7 cells with IC50 values of 15.41 and 12.99 µM, respectively. None of the compounds analyzed significantly affected the viability of peripheral blood mononuclear cells. Also, significant induction of apoptosis was observed when both cancer cell lines were incubated with compounds 6 and 12. In MCF-7 cells, treatment with these compounds led to cell cycle arrest in the G0/G1 phase. The results obtained suggest that these structures may be useful in developing new therapies for malaria and cancer treatment.

The Role of Chloroquine and Hydroxychloroquine in Immune Regulation and Diseases.

Chloroquine (CQ) and hydroxychloroquine (HCQ) are derivatives of the heterocyclic aromatic compound quinoline. These economical compounds have been used as antimalarial agents for many years. Currently, they are used as monotherapy or in conjunction with other therapies for the treatment of autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren's syndrome (SS) and antiphospholipid antibody syndrome (APS). Based on its effects on the modulation of the autophagy process, various clinical studies suggest that CQ and HCQ could be used in combination with other chemotherapeutics for the treatment of various types of cancer. Furthermore, the antiviral effects showed against Zika, Chikungunya, and HIV are due to the annulation of endosomal/lysosomal acidification. Recently, CQ and HCQ were approved for the U.S. Food and Drug Administration (FDA) for the treatment of infected patients with the coronavirus SARSCoV- 2, causing the disease originated in December 2019, namely COVID-2019. Several mechanisms have been proposed to explain the pharmacological effects of these drugs: 1) disruption of lysosomal and endosomal pH, 2) inhibition of protein secretion/expression, 3) inhibition of antigen presentation, 4) decrease of proinflammatory cytokines, 5) inhibition of autophagy, 6) induction of apoptosis and 7) inhibition of ion channels activation. Thus, evidence has shown that these structures are leading molecules that can be modified or combined with other therapeutic agents. In this review, we will discuss the most recent findings in the mechanisms of action of CQ and HCQ in the immune system, and the use of these antimalarial drugs on diseases.

Agentes dopaminérgicos centrales análogos N-aralquil metoxilados del 2-aminoindano / Central dopaminergic agents analogues of N-aralkyl methoxylated of 2-aminoindane

RESUMEN La neurotransmisión dopaminérgica interviene en los mecanismos que involucran los procesos motores, cognoscitivos, conductuales y neurocrinos y su mal funcionamiento la involucra en los trastornos neurodegenerativos que afectan al sistema nervioso central (SNC), tales como en la enfermedad de Parkinson y la enfermedad de Huntington, entre otras. Con el propósito de encontrar una solución terapéutica a estas patologías, en publicaciones anteriores hemos reportado la síntesis, la evaluación farmacológica y el estudio teórico computacional de los compuestos análogos mono y dihidroxilados (sobre el anillo indano) del N-aralquil-2-aminoindano 4-8, análogos 4,7-dimetoxi-2-aminoindano-N-aralquil, bajo sus formas metoxiladas sobre el anillo bencénico del fragmento aralquil 9 y el derivado fenólico 10, así como también los análogos diclorados del N-aralquil-2-aminoindano 11 con actividades dopaminérgicas centrales. En el presente trabajo se sintetizaron los clorhidratos del 2-aminoindano- N-[2-(mono o dimetoxi)-fenil)-1-metil-etil] 12-15 y su evaluación farmacológica mostraron respuestas agonísticas como potenciales agentes antihuntington y antipárkinson.

SUMMARY Dopaminergic neurotransmission is implicated in mechanisms that involve motor, cognoscitive, conductual and neurocrine process, and its malfunction involucrates it in neurodegenerative disorders affecting central nervous system (CNS), like Parkinson's disease and Huntington's disease, among others. On the purpose of finding some therapeutic for these pathologies, in previous researches we have reported synthesis, pharmacological evaluation and theoretical computational study of compounds analogues mono or di hydroxilated (on indane ring) of N-aralkyl-2-aminoindane 4-8, analogues 4,7-dimethoxy-2-aminoindane-N-aralkyl, under its methoxylated forms on benzene ring of aralkyl fragment 9 and phenolic derivate 10, also dichlorade analogs of N-aralkyl-2-aminoindane 11 with central dopaminergic activities. In this work were synthesized hydrochlorides of 2-aminoindane-N-[(mono or di methoxy)-phenyl-1-methyl-ethyl] (12-15) and its pharmacologic evaluation showed agonistic responses as potential agents anti Huntington and/or anti Parkinson.

Optimization of antimalarial, and anticancer activities of (E)-methyl 2-(7-chloroquinolin-4-ylthio)-3-(4-hydroxyphenyl) acrylate.

Chemically modified versions of bioactive substances, are particularly useful in overcoming barriers associated with drug formulation, drug delivery and poor pharmacokinetic properties. In this study, a series of fourteen (E)-methyl 2-(7-chloroquinolin-4-ylthio)-3-(4-hydroxyphenyl) acrylate (2-15) were prepared by using a one step synthesis from 1 previously described by us as potential antimalarial and antitumor agent. Molecules were evaluated as inhibitors of ß-hematin formation, where most of them showed a significant inhibition value (% > 70). The best inhibitors were tested in vivo as potential antimalarials in mice infected with P. berghei ANKA, chloroquine susceptible strain. Three of them (5, 6, and 15) displayed antimalarial activity comparable to that of chloroquine. Also, molecules were evaluated for their cytotoxic activity against two human cancer cell lines (Jurkat E6.1 and HL60) and primary culture of human lymphocytes. Most of the synthesized compounds, except for analogs 2-6, 8, and 10-12, displayed cytotoxicity against cancer cell lines without affecting normal cells. The potency of the compounds was 15 ≫ 1, and 14 > 7, 9, and 13. Flow cytometry analysis demonstrated an increase in apoptotic cell death after 24 h. The compounds may affect tumor cell autophagy and consequently increase cell apoptosis.

Novedoso profármaco derivado de la lilolidina con actividad dopaminérgica central / Novel prodrug derivative from lilolidine with central dopaminergic activity

La desregulación de la neurotransmisión dopaminérgica central ha sido relacionada con enfermedades neurodegenerativas, tales como la enfermedad de Parkinson y la Corea de Huntington. En las últimas décadas son muchos los compuestos con actividad dopaminérgica central que se han diseñado, sintetizado y evaluado farmacológicamente y, a pesar de estos esfuerzos, no se ha logrado obtener un fármaco efectivo capaz de mejorar o curar estas patologías. Con el fin de contribuir en esta búsqueda primordial, en el presente trabajo se describe el diseño, la síntesis y la evaluación farmacológica del derivado de la lilolidina, clorhidrato de 6-(2-aminoindanil)-N-(2,4,5,6-tetrahidro-1H-pirrolo[3,2,1-ij]quinolina) 4 (MAIL), con el propósito de restablecer la homeostasis de la transmisión dopaminérgica en la enfermedad de Parkinson y/o la Corea de Huntington. Para ello, se utilizaron las diferentes estrategias nigroesclásicas y heterocíclicas enmarcadas en la síntesis orgánica a través de una ruta convergente. Asimismo, se realizó la evaluación farmacológica preliminar, al determinar el comportamiento estereotipado en ratas Sprague-Dawley cuando les fue administrado el derivado de la lilolidina, por las vías ICV (intracerebroventricular) e IE (intraestriatal). Los resultados obtenidos del compuesto 4 mostraron una acción central como agonista, a través de mecanismos dopaminérgicos.

Central dopaminergic neurotransmission deregulation has been related with neurodegenerative sicknesses, like Parkinson’s disease and Huntington’s Chorea. During the last decades, many compounds with dopaminergic activity have been designed, synthesized and pharmacologically evaluated, but despite all these efforts, an effective drug able to improve or cure these pathologies has not been achieved. With the purpose to contribute in this essential search, this work describes the design, synthesis and pharmacological evaluation of the lilolidine derivative, 6-(2-aminoindanyl)-N-(2,4,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinoline hydrochloride) 4 (MAIL), with the purpose of restoring the homeostasis of dopaminergic transmission in Parkinson’s disease and/or Huntington’s Chorea. To perform that, different organic synthesis classic and heterocyclic strategies were employed through a convergent route. Also, a preliminar pharmacological evaluation was done, where the stereotyped behavior of Sprague-Dawley rats was studied after the ICV (intracerebroventricular) and IE (intrastriatum) administration of the lilodine derivative. The results obtained of compound 4 showed a central dopaminergic agonist activity through dopaminergic mechanisms.

Novedosos agentes dopaminérgicos centrales derivados del 2-aminoindano-4,7 disustituido atípico. Síntesis y perfil farmacológico central / Novel central dopaminergic agents derived from atypical di-substituted 2-aminoindane-4, 7. Synthesis and central pharmacological profile

En las últimas décadas son muchos los compuestos con actividad dopaminérgica central que se han diseñado, sintetizado y evaluado farmacológicamente. A pesar de ello, no se ha logrado obtener un fármaco capaz de mejorar o curar las patologías que involucran la regulación dopaminérgica en el sistema nervioso central tales como la Enfermedad de Parkinson y la esquizofrenia, entre otras. Tomando en consideración el término de “farmacóforo atípico” y a partir del compuesto 5, se incorporó el fragmento aralquil y se sintetizaron los compuestos 10, 11, 13a-h y 14a-h. Tanto los compuestos 10 y 13a-h bajo su forma metoxilada como los compuestos 11 y 14a-h bajo su forma fenólica, fueron evaluados farmacológicamente para determinar su actividad agonística y antagonística sobre el sistema dopaminérgico central. Para ello se determinó el efecto de la inyección intracerebroventricular de dichos compuestos sobre el balance hidromineral y la conducta estereotipada en ratas. Los resultados de la evaluación farmacológica preliminar muestran una acción central a través de mecanismos dopaminérgicos, siendo que los compuestos 10, 11, 13d-h y 14a mostraron respuestas como agonistas, mientras que los compuestos 14b-h, tuvieron respuestas como antagonistas.

In recent decades, many compounds with central dopaminergic activity have been designed, synthesized and evaluated pharmacologically. However, it has not been possible to obtain a drug able to improve or cure diseases involving dopaminergic regulation in the central nervous system, such as Parkinson’s disease and schizophrenia, among others. Taking into consideration the term “atypical pharmacophore” and from the compound 5, the aralkyl fragment was incorporated, and the compounds 10, 11, 13a-h and 14a-h were synthesized. Both the compounds 10 and 13a-h under its methoxylated form and the compounds 11 and 14a-h under the phenolic form, were evaluated to determine their pharmacologically agonistic and antagonistic effects on central dopaminergic activity. For this, the effect of intracerebroventricular injection of said compounds on the hydromineral balance and stereotyped behavior in rats, was determined. The results of the preliminary pharmacological evaluation show a centrally acting action through dopamine mechanisms, in which the compounds 10, 11, 13d-h and 14a showed responses as agonists, whereas compounds 14b-h, had responses as antagonists.

Synthesis, crystal structure and effect of indeno[1,2-b]indole derivatives on prostate cancer in vitro. Potential effect against MMP-9.

A highly regiospecific synthesis of a series of indenoindoles is reported, together with X-ray studies and their activity against human prostate cancer cells PC-3 and LNCaP in vitro. The most effective compound 7,7-dimethyl-5-[(3,4-dichlorophenyl)]-(4bRS,9bRS)-dihydroxy-4b,5,6,7,8,9bhexahydro-indeno[1,2-b]indole-9,10-dione 7q reduced the viability in both cell lines in a time and dose-dependent manner. Inhibitory effects were also observed on the adhesion, migration, and invasion of the prostate cancer cells as well as on clonogenic possibly by inhibition of MMP-9 activity. Molecular docking of 7q and 6k into MMP-9 human active site was also performed to determine the probable binding mode.

N'-Formyl-2-(5-nitrothiophen-2-yl)benzothiazole-6-carbohydrazide as a potential anti-tumour agent for prostate cancer in experimental studies.

OBJECTIVES: Benzothiazoles (BZTs) represent organic compounds with different biological actions. In this study we aimed to investigate ten newly synthesized BZT derivatives as potential anti-tumour agents against prostate cancer in vitro and in vivo. METHODS: The cytotoxic effect of these compounds was screened on the human prostate cancer cell lines PC-3 and LNCaP. The most effective compound, N'-formyl-2-(5-nitrothiophen-2-yl)benzothiazole-6-carbohydrazide, was further characterized regarding its dose- and time-dependent effects on cell viability and proliferation (XTT test) as well as on adhesion and spreading (real-time cell analyzer xCelligence), migration (scratch-wound repair assay) and invasion (Boyden chamber) of the cells. This BZT derivative was also tested as an inhibitor of angiogenesis (chicken chorioallantoic membrane assay), clonogenic activity (soft agar) and matrix metalloproteinase 9 (gelatin zymography). KEY FINDINGS: N'-Formyl-2-(5-nitrothiophen-2-yl)benzothiazole-6-carbohydrazide significantly inhibited all tested properties of the prostate cancer cell lines and showed low toxic in vitro and in vivo effects. The in vitro anti-tumour activity of this compound was confirmed by the in vivo effects on PC-3 xenografts in nude mice. Tumour growth was decreased in treated compared with untreated mice. CONCLUSIONS: These results suggest the potential capacity of BZTs and in particular N'-formyl-2-(5-nitrothiophen-2-yl)benzothiazole-6-carbohydrazide as anti-tumour agents for the treatment of prostate cancer.

Potential antitumour and pro-oxidative effects of (E)-methyl 2-(7-chloroquinolin-4-ylthio)-3-(4-hydroxyphenyl) acrylate (QNACR).

CONTEXT: Characterization of the pro-oxidant activity of QNACR. OBJECTIVES: Reactive oxygen species (ROS) induce cellular damage and represent unique opportunities to kill malignant cells. In this study, we synthesized and evaluated the new compound, (E)-methyl 2-(7-chloroquinolin-4-ylthio)-3-(4-hydroxyphenyl) acrylate (QNACR) as potential pro-oxidative agent against breast cancer. METHODS: Oxidative stress biomarkers such as ROS, thiobarbuturic acid reactive species (TBARs) and different antioxidant enzyme activities were determined in cell lysates. RESULTS: QNACR showed cytotoxic and more selective effects to tumour MCF7 cells (IC50 < 25 µM) compared to antitumour controls, inducing ROS and TBARs parallel to inhibitions of catalase (CAT), glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH). Longer exposures to QNACR triggered adaptive effects increasing the overall activities of CAT, glutathione reductase, G6PDH and 6PGDH, but eventually the adaptation changes faded and cells died. CONCLUSION: QNACR led to remarkable modifications in the oxidative status of tumour cells, proposing this compound as potential alternative for antitumour therapy.

Cytotoxic effects of N'-formyl-2-(5-nitrothiophen-2-yl) benzothiazole-6-carbohydrazide in human breast tumor cells by induction of oxidative stress.

Chemically active molecules, such as reactive oxygen species (ROS), are prone to induce cellular damage by oxidative stress and this could be exploited as a strategy to kill malignant cells. In this study, we evaluated the antitumor activity of a new compound, N'-formyl-2-(5-nitrothiophen-2-yl)benzothiazole-6-carbohydrazide (FBZC) by assessing its pro-oxidant effects on breast cancer in vitro. Oxidative stress, generated by FBZC, was characterized by measuring reactive species and antioxidant enzymes and markers. Results showed that the cytotoxic effects of FBZC on MCF7 breast cancer cells (half inhibitory concentration of 5.4 µg/ml), were partially reversed by the addition of regular antioxidants. FBZC induced ROS and lipid peroxidation, together with a significant inhibition of superoxide dismutase, glutathione reductase and total glutathione levels as well as increases in catalase and glutathione-S-transferase activities, in an acute fast response. Thus, the antitumor effects of FBZC could be related to oxidative deregulation due to a combination of induction of ROS generation and inhibition of key antioxidant enzymes.

Synthetic studies toward C-glucosidic ellagitannins: a biomimetic total synthesis of 5-O-desgalloylepipunicacortein†A.

C-glucosidic ellagitannins constitute a subclass of bioactive polyphenolic natural products with strong antioxidant properties, as well as promising antitumoral and antiviral activities that are related to their capacity to interact with both functional and structural proteins. To date, most synthetic efforts toward ellagitannins have concerned glucopyranosic species. The development of a synthetic strategy to access C-glucosidic ellagitannins, whose characteristic structural feature includes an atropoisomeric hexahydroxydiphenoyl (HHDP) or a nonahydroxyterphenoyl (NHTP) unit that is linked to an open-chain glucose core by a C-aryl glucosidic bond, is described herein. The total synthesis of the biarylic HHDP-containing 5-O-desgalloylepipunicacortein A (1 ß) was achieved by either using the natural ellagic acid bis-lactone as a precursor of the requested HHDP unit or by implementing an atroposelective intramolecular oxidative biarylic coupling to forge this HHDP unit. Both routes converged in the penultimate step of this synthesis to enable a biomimetic formation of the key C-aryl glucosidic bond in the title compound.

Effect of quinolinyl acrylate derivatives on prostate cancer in vitro and in vivo.

Quinolines and acrylates are chemical compounds which were previously described as potential antitumor agents. In this study, a series of seven new quinolinyl acrylate derivatives were synthesized and evaluated against human prostate cancer cells PC-3 and LNCaP in vitro and in vivo. The most effective compound (E)-methyl 2-(7-chloroquinolin-4-ylthio)-3-(4 hydroxyphenyl) acrylate reduced the viability in both cell lines in a time- and dose-dependent manner. Inhibitory effects were also observed on the adhesion, migration, and invasion of the prostate cancer cells as well as on the neoangiogenesis, clonogenic and MMP-9 activity. The effect in vivo was studied in PC-3 xenografts in nude mice. The results were concordant with the in vitro effects and showed decreased tumor growth in treated animals compared to controls. The study suggests the multi-target efficacy of the quinolinyl derivate against human prostate cancer cells and supports its potential therapeutic usefulness.