Serotonin (5-HT) and dopamine (DA) are key neurotransmitters in the central nervous system (CNS) that are involved in the regulation of behavior. Dysfunction of dopaminergic and serotonergic neurotransmitter pathways, which are responsible for the regulation of mood, cognition, and movement, can lead to a wide range of brain disorders, both neurological and psychiatric. DA is implicated in various neurodegenerative and neuropsychiatric diseases, and dopaminergic systems in the brain are known to receive serotonergic innervation. In the present study, we present the synthesis and preliminary pharmacological evaluation of the compounds N-[(2-chloro-quinolin-3-yl) methyl]methyladamantane (7) and amino-methyladamantane (10), which were found to have dopaminergic and serotonergic activities in the central nervous system. The strategy used in the design of hybrid compound 7 led to the development of a novel agent with antipsychotic and/or anxiolytic activity. Compound 10 only showed antiparkinsonian activity. These compounds contribute to the pharmacological arsenal for the treatment of pathologies related to neurodegenerative and neuropsychiatric disorders.

Serotonin (5-HT) and dopamine (DA) are key neurotransmitters in the central nervous system (CNS) that are involved in the regulation of behav-ior. Dysfunction of dopaminergic and serotonergic neurotransmitter pathways, which are responsible for the regulation of mood, cognition, and movement, can lead to a wide range of brain disorders, both neurological and psychiatric. DA is implicated in various neurodegenerative and neuropsychiatric diseases, and dopaminergic systems in the brain are known to receive serotonergic in-nervation. In the present study, we present the synthesis and preliminary phar-macological evaluation of the compounds N-[(2-chloro-quinolin-3-yl) methyl]-methyladamantane (7) and amino-methyladamantane (10), which were found to have dopaminergic and serotonergic activities in the central nervous system. The strategy used in the design of hybrid compound 7 led to the development of a novel agent with antipsychotic and/or anxiolytic activity. Compound 10 only showed antiparkinsonian activity. These compounds contribute to the pharma-cological arsenal for the treatment of pathologies related to neurodegenerative and neuropsychiatric disorders.

Dopamine 1 is involved in neurodegenerative disorders affect-ing 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 de-rivatives have shown selective activity in the central dopaminergic system. Both the N-[(2,4-dichlorophenyl)-1-methyl-ethyl]-2-aminoindane hydrochloride 2and 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 phar-macological 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.

Dopamine 1 is involved in neurodegenerative disorders affect-ing 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 de-rivatives 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 phar-macological 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.

Photoredox-catalyzed addition of the difluoromethylradical to unactivated alkenes has been found to trigger neophyl-like aryl and heteroaryl migrations which allowed the construction of a diverse series of difluoromethyl ketones. The reaction featured mild reaction conditions and broad substrate scope.

Diverse models of intramolecular charge transfer (ICT) have been proposed for interpreting the origin of the charge-transfer (CT) state in donor-acceptor (D-A) dyes. However, a large variety of fused-heterocyclic dyes containing a pseudo-aromatic ring in the rigid structure have shown to be incompatible with them. To approximate a solution within the ICT concept, we reported a novel ICT model called partially aromatized intramolecular charge transfer (PAICT). PAICT involves the generation of a CT state from an ICT that occurred within a pre-excited D-A fused-heterocyclic structure possessing a pseudo-aromatic or unstable aromatic ring as the acceptor moiety. The model was proposed from the multiple-emissive mesomeric D-A N-1-aryl-2-(trifluoromethyl)benzo[b][1,8]naphthyridin-4(1H)-one, whose excited mesomeric states, which are defined by the aromatic and pseudo-aromatic forms of the pyrindin-4(1H)-one ring, led to a common partial aromatized CT state upon excitation via PAICT. The latter was supported through theoretical calculations on the excited mesomeric states, one-dimensional (1D) and two-dimensional (2D) excitation-emission measurements in different solvents, and the detection of three excited states by lifetime measurements upon 370 nm excitation. The existence of mesomerism was supposed from: (i) two overlapping bands at 370-390 (or 400-420 nm) in UV-vis spectra, (ii) the direct interaction between the pyridinic nitrogen of one molecule and the carbonylic oxygen of the other found in the solid state and, (iii) the detection of three excited states by lifetime measurements. The PAICT opens new perspectives for interpreting the charge-transfer phenomenon in fused-heterocyclic dyes, in particular, those containing a pseudo-aromatic or unstable aromatic ring as an acceptor moiety.

1,1-Bis(dimethylamino)-2,2-difluoroethene has been shown to be a diverse and highly effective building block for the preparation of a variety of fluorinated compounds. Reported here are preliminary results of its use for acylation reactions with acyl chlorides to form 2,2-difluoroketoacetamides as well as for its direct condensation with various acidic a-hydrogen carbon compounds to form a variety of functionalized difluoromethyl enamines.

Las enfermedades neurodegenerativas y neuropsiquiátricas se encuentran directamente relacionadas con alteraciones o disfuncionalidad delsistema dopaminérgico central. Entre las primeras encontramos la enfermedad de Parkinson (EP), la disquinesia tardía, el síndrome de Tourette, la Corea de Huntington (EH), y entre las segundas la Esquizofrenia (EZ), la adicción, la manía,la depresión, y los desórdenes de la alimentación. Con el fin de contribuir con el arsenal terapéutico que permita restaurar la homeostasis de la neurotransmisión dopaminérgica central, se evaluó farmacológicamente el clorhidratodel 1-amino-6,7,8,8a-tetrahidroacenafteno 2 (Ja116a) mediante la cuantificación de sus efectos sobre la conducta estereotipada de ratas. Se emplearon ratas machos de la cepa Sprague-Dawley, a las que se les implantó una cánula intracerebroventricular (ICV). El compuesto 2 (Ja116a) fue administrado porvía ICV (5μg/5μL y 50μg/5μL), en presencia o ausencia de apomorfina (APO),haloperidol (HAL), buspirona (BUS) o ziprasidona (ZIP); o por vía intraperitoneal(IP) (1mg/Kg) en ratas tratadas con APO o HAL. Igualmente, un grupo de ratas fue sometido a denervación dopaminérgica central mediante la 6OH-dopamina(6OHDA). Los resultados mostraron que Ja116a induce una conducta estereotipada de roídas y olfateos (sistema extrapiramidal) y acicalamientos y lamidas (sistema límbico), efectos que fueron bloqueados por el HAL y reducidospor la buspirona y la 6OHDA. Estos hallazgos indican que Ja116 actúa principalmente como un agonista dopaminérgico postsináptico, por lo que podría proponerse como un fármaco novedoso para el tratamiento de enfermedades neurodegenerativas tales como la Enfermedad de Parkinson.

Neurodegenerative and neuropsychiatric diseases are directly related to alterations or dysfunction of the central dopaminergic system. Among the first are Parkinson's disease (PD), tardive dyskinesia, Tourette's syndrome, Huntington's chorea (HD), and among the second, Schizophrenia (EZ), addiction, mania, depression, and eating disorders. In order to contribute to the therapeutic arsenal that allows restoring the homeostasis of central dopaminergic neurotransmission, 1-amino-6,7,8,8a-tetrahydro acenaphthene 2 hydrochloride (Ja116a) was pharmacologically evaluated by quantification of its effects on stereotyped behavior in rats. Male Sprague-Dawley rats were used and were implanted with an intracerebroventricular cannula (ICV). Compound Jall6a was ICV administered (5 mu g/5 mu L and 5 mu g/5 mu L), in the presence or absence of apomorphine (APO); haloperidol (HAL); buspirone (BUS) or ziprasidone (ZIP); or intraperitoneally (IP) (1mg/Kg) in rats treated with APO or HAL. Similarly, a group of rats was subjected to central dopaminergic denervation by 6OH-dopamine (6OHDA). The results show that Jal 16a induces a stereotypical behavior of gnawing and sniffing (extrapyramidal system) and grooming and licking (limbic system), effects that were blocked by HAL and reduced by buspirone and 6OHDA. These findings indicate that Ja116 acts mainly as a postsynaptic dopaminergic agonist, so it could be proposed as a novel drug for the treatment of neurodegenerative diseases such as Parkinson's disease.

A series of six 3-aryl-6-(N-methylpiperazin)-1,2,4-triazolo[3,4-a]phthalazines were prepared through a facile and efficient one-pot copper-catalyzed procedure from 4-chloro-1-phthalazinyl-arylhydrazones with relatively good yields (62-83%). The one-pot copper-catalytic procedure consists of two simultaneous reactions: (i) a direct intramolecular dehydrogentaive cyclization between ylidenic carbon and adjacent pyrazine nitrogen to form 1,2,4-triazolo ring and, (ii) a direct N-amination on carbon-chlorine bond. Then, an in vitro anticancer evaluation was performed for the synthesized compounds against five selected human cancer cells (A549, MCF-7, SKBr3, PC-3 and HeLa). The nitro-derivatives were significantly more active against cancer strains than against the rest of tested compounds. Specifically, compound 8d was identified as the most promising anticancer agent with significant biological responses and low relative toxicities on human dermis fibroblast. The cytotoxic effect of compound 8d was more significant on PC3, MCF-7 and SKBr3 cancer cells with low-micromolar IC50 value ranging from 0.11 to 0.59 μM, superior to Adriamycin drug. Mechanistic experimental and theoretical studies demonstrated that compounds 8d act as a K+ channel inhibitor in cancer models. Further molecular docking studies suggest that the EGFR Tyrosine Kinase enzyme may be a potential target for the most active 3-aryl-6-(N-methylpiperazin)-1,2,4-triazolo[3,4-a]phthalazines.

A visible-light mediated approach to radical difluoromethylation of 3- and 3,5-substituted indoles was investigated using a readily synthesized difluoromethyl source, CF2HPPh3Br. Direct difluoromethylation of indoles in the two position is a rare feat in the literature. The reactions were conducted at room temperature, using Ir (ppy)(3) as photocatalyst in acetone, to afford the 2-difluoromethyl indoles in relatively low to moderate yields.

To identify new agents for the treatment of American cutaneous leishmaniasis, a series of eight 1,4-bis(substituted benzalhydrazino)phthalazines was evaluated against Leishmania braziliensis and Leishmania mexicana parasites. These compounds represent a disubstituted version of the 1-chloro-4-(monoaryl/heteroarylhydranizyl)phthalazine that exhibited a significant response against L. braziliensis according to our previous findings. Two disubstituted phthalazines 3b and 3f were identified as potential antileishmanial agents against L. braziliensis parasites, exhibiting a submicromolar IC50 response of 2.37 and 7.90 µM on the promastigote form, and of 1.82 and 4.56 µM against intracellular amastigotes, respectively. In particular, compound 3b showed interesting responses against amastigote isolates from reference, glucantime-resistant and clinical human strains, which were by far superior to the biological response found for the glucantime drug. With regard to the toxicity results, both 3b and 3f exhibited moderate LD50 values against murine macrophages (BMDM), with good selectivity indexes on promastigotes and intracellular amastigotes of L. braziliensis. A comparison of biological response was established between the monosubstituted and disubstituted versions of these benzalhydrazino-phthalazines. Easy synthetic procedure and significant response against amastigote strains including against resistant lines made compound 3b a potential candidate for further pharmacokinetic and in vivo experiments as antileishmanial agent, and as a platform for further structural optimization. Mechanism-of-action studies and molecular docking simulations discarded to inhibition of superoxide dismutase as possible mode of action.

Neurodegenerative disorders such as Parkinson and Huntington Chorea are related with damage to the central dopaminergic system. On the purpose to find new drugs able to re-establish the imbalance on the dopaminergic neurotransmission in the central nervous system and counteract some of the neurodegenerative sicknesses, we have designed, synthesized, pharmacologically evaluated, and studied through molecular modeling,2-aminoindane-quinoline analog derivatives (1–5). Pharmacological studies made on the central nervous system through ICV (intracerebroventricular) and IS (intrastriatal), of compounds (1–5) showed agonistic activity by the activation of dopaminergic mechanisms on the central nervous system. The corresponding molecular modeling study permitted us not only to explain the differential behavior of studied compounds, but also to understand whichmolecular interactions are responsible to stabilize the different complexes formed between those compounds and the D2 receptor. These results validate our medicinal chemical approach in different aspects: the receptor model used, the responsible fragment inserted within the structure of the compounds capable of interacting with the receptor, the complementary functional groups that facilitate the expected response and the pharmacological administration routes. All these aspects are important for the design of this type of compounds as potential anti-Parkinson and/or anti-Huntington agents.

Traditional antimalarial drugs based on 4-aminoquinolines have exhibited good antiproliferative activities against Leishmania parasites; however, their clinical use is currently limited. To identify new 4-aminoquinolines to combat American cutaneous leishmaniasis, we carried out a full in vitro evaluation of a series of dehydroxy isoquines and isotebuquines against two Leishmania parasites such as Leishmania braziliensis and Leishmania mexicana. First, the antiproliferative activity of the quinolines was studied against the promastigote forms of L. braziliensis and L. mexicana parasites, finding that five of them exhibited good antileishmanial responses with micromolar IC50 values ranging from 3.84 to 10 μM. A structure-activity relationship analysis gave evidence that a piperidine or a morpholine attached as N-alkyamino terminal substituent as well as the inclusion of an extra phenyl ring attached at the aniline ring of the isotebuquine core constitute important pharmacophores to generate the most active derivatives, with antileishmanial responses by far superior to those found for the reference drug, glucantime. All compounds showed a relatively low toxicity on human dermis fibroblasts, with CC50 ranging from 69 to >250 μM. The five most active compounds displayed moderate to good antileishmanial activity against the intracellular amastigote form of L. braziliensis, compared to the reference drug. In particular, compound 2j was identified as the most potent agent against antimony-resistant amastigotes of L. braziliensis with acceptable biological response and selectivity, emerging as a promising candidate for further in vivo antileishmanial evaluation. Diverse mechanism-of-action studies and molecular docking simulations were performed for the most active 4-aminoquinoline.

Diverse dehydroxy-isotebuquine derivatives were prepared by using a five step synthetic sequence in good yields. All these new 4-aminoquinolines were evaluated as inhibitors of haemozoin formation, where most of them showed a significant inhibition value (% IHF >97). The best inhibitors were tested in vivo as potential antimalarials in mice infected with Plasmodium berghei ANKA chloroquine susceptible strain, three of them (11b, 11d and 11h) displayed an antimalarial activity comparable to that of chloroquine.

Trifluoromethyl-substituted quinolones and their analogues have emerged as an interesting platform in the last 6 years to design antiparasite agents. Many of their derivatives have been demonstrated to display excellent efficacy against flagellate parasites such as Plasmodium spp. In order to identify new analogues of trifluoromethyl-substituted quinolones to treat the American cutaneous leishmaniasis, we evaluated the antiproliferative activity of a series of 2-(trifluoromethyl)benzo[b]-[1,8]naphthyridin-4(1H)-ones on the Leishmania braziliensis and Leishmania mexicana parasites. The mentioned derivatives have never been evaluated against any parasite strain. In general, an in vitro evaluation on L.(L)mexicana and L.(V)braziliensis showed that L.(L)mexicana was more sensitive to the action of the compounds than L.(V)braziliensis, either in the promastigote or in the amastigote form. Five compounds exhibited moderate efficacy against L.(L)mexicana promastigotes, with IC50 values ranging from 9.65 to 14.76 µM. From the mentioned molecules, three compounds, 1e, 1f, and 1h, showed a discrete response against axenic and intracellular amastigotes, with LD50 values between 19 and 24 µM. Moreover, an in vitro evaluation was performed on an antimony-resistant amastigote strain and a human isolate amastigote strain. These three compounds showed discrete toxicity on peritoneal macrophages; however, their relatively good antiamastigote response compared to the drug glucantime promoted our trifluoromethyl-substituted benzo[b][1,8]naphthyridin-4(1H)-ones as a potential platform to design potent antileishmanial agents.

Traditional antimalarial drugs based on 4‐aminoquinolines have exhibited good antiproliferative activities against human tumor cells; however, their low relative efficacy has limited their corresponding clinical uses. In order to identify new potent anticancer agents based on 4‐aminoquinoline, we evaluated the antiproliferative activity of a series of dehydroxy isoquines and isotebuquines against five human cancer lines. HeLa and SKBr3 were significantly more sensitive to the action of tested quinolines than the A549, MCF‐7, and PC‐3 cancer lines. Compound 2h was by far the most potent derivative against four of the tested lines (except to PC3 line), exhibiting low micromolar or nanomolar IC50 values superior to adriamycin reference, low toxicities on dermis human fibroblasts (LD50 > 250 μM), and excellent selectivity indexes against the mentioned cancer cells. A structure–activity relationship analysis put in evidence that a pyrrolidine or morpholine moiety as N‐alkyl terminal substitution and the incorporation of the extra phenyl attached to aniline ring are pharmacophore essentials for improvement the anticancer activity of the studied dehydroxy isoquines and isotebuquines. From the results, compound 2h emerged as a promising anticancer candidate for further in vitro assays against resistant‐strain and in vivo studies as well as pharmacokinetic and genotoxicity studies. Mechanistic assays suggested that the most active quinoline 2h act as calcium‐activated potassium channel activator.

Background: Neurodegenerative, neurological and mental disorders, as well as substance abuse have a worldwide high incidence rate, becoming relevant factors that contribute to premature morbidity and mortality. Dopamine is well known to be involved in these pathologies. The key focus in the search for new drugs, that alleviate or cure these diseases, is pursuing the design of compounds with both efficacy and fewer adverse effects in order to obtain novel agents capable of restoring the homeostasis in the CNS of dopaminergic neurotransmission and counteracting some of neurodegenerative and neuropsychiatric diseases, such as Parkinson's disease, schizophrenia, Huntington's chorea and drug addictions. Methods: the compounds 11,12H-dihydronaphthalene[1,2-b] quinoline 2a and 9-methoxy-11,12H-dihydronaphthalene [1,2-b] quinoline 2b were designed and synthesized. The organic synthesis was performed according to the outlined synthesis strategies, together with a pharmacological evaluation of the male Sprague-Dawley rats. Results: Compound structures were confirmed by H-1, C-13, DEPT and HETCOR NMR. Pharmacological testing and computational studies validated the asserted medicinal-chemical approach for their design, showing compound 2a acting as an atypical dopamine antagonist. Conclusion: The study showed that compound 2a has an atypical antagonistic action on the central dopaminergic system. These pharmacological and computational-theoretical results support the suitability of the medicinal chemical approach in the design of this compound.

With the aim to identify a potential drug candidate to treat cutaneous leishmaniasis, a series of 1-phthalazinyl hydrazones were synthesized and tested against Leishmania braziliensis parasite, one of the main responsible of this disease in the world. A structure-activity relationship permitted to identify two phthalazines containing nitroheterocyclic moiety 3l and 3m as promising new lead compounds. These compounds showed a significant antileishmanial activity against promastigote form of L. braziliensis, with EC50 values in sub-micromolar and nanomolar ranges. The phthalazine 3l also displayed a selective and excellent activity against the clinically relevant intracellular amastigotes form, with a EC50 value in sub-micromolar range (0.59 μM), without affecting the viability of the host cells. Oxidative stress was identified as the possible mode of action of the most active phthalazine. Considering their significant antileishmanial activity and ease synthesis, the phthalazine containing nitroheterocyclic represents a promising agent against Leishmania braziliensis for the rational design of new leads.