We describe a short synthetic route to a new series of 7-chloroquinoline hybrids derived from albendazole-, thioacetazone-, and primaquine-based drugs. The design strategy incorporated a ureido group as a bioisostere of known inhibitors of β-hematin formation (βHF). Compounds 13–34 were characterized by infrared (IR), nuclear magnetic resonance (NMR), and elemental analysis. Preliminary in vitro screening identified compounds 13, 14, 16–18, and 27–29 as inhibitors of βHF. Among these, compound 16 was the most active, exhibiting 90.68% ± 0.043% inhibition of βHF compared with 92.55% ± 0.019% for chloroquine (CQ). In vivo evaluation in Plasmodium berghei ANKA, a CQ-susceptible murine malaria strain, revealed that compound 16 reduced parasitemia to 1.2% ± 0.12% and extended survival to 27.33 ± 0.15 days. This compares favorably with chloroquine (parasitemia: 0.88% ± 0.09%; survival: 29.6 ± 0.13 days). Furthermore, at a tested concentration of 10 mM, compound 16 showed 17.23 ± 0.13 hemolysis, compared to 29.65 ± 0.10% for CQ, indicating no marked lytic action on erythrocytes. This study evaluated the hepatological consequences of malaria infection in mice infected with P. berghei. Based on its potent in vitro and in vivo activity, favorable hemolytic profile, and hepatoprotective effects, compound 16 emerges as a promising new candidate for antimalarial development.

La Organización Mundial de la Salud (OMS), recomienda la administración de combinaciones entre antimaláricos convencionales entre sí, con otros de distinta indicación terapéutica, y con plantas medicinales por sus efectos pleiotrópicos. En virtud de tal contexto, en este trabajo, se propone evaluar el potencial antimalárico de la Cloroquina (CQ), quinolina usada en el tratamiento de la malaria, y su combinación con el extracto acuoso de la hoja de Azadirachta indica A. Juss (NEEM), con la finalidad de potenciar la actividad antimalárica de la CQ. A tales efectos, utilizando el modelo de infección no patente de ratones de la cepa INH con Plasmodium berghei, se ensayaron las distintas combinaciones CQ20 mg/Kg + EAN 10mg/Kg (CQ20+EAN10) y la CQ 20mg/Kg + EAN 20mg/Kg (CQ20+EAN20) utilizando la Prueba de Peter, según la cual los ratones infectados con Plasmodium berghei (106 parásitos por ratón, vía i.p), se trataron con las combinaciones en estudio durante 5 días (1 dosis diaria, por 5 días, vía i.p.), iniciando el tratamiento 2 horas post infección. Se determinó el porcentaje de parasitemia al 5to día post infección, y se registró los días de sobrevivencia de los animales infectados y tratados (DSP), comparados con los controles infectados y no tratados, durante 30 días. Las combinaciones (CQ20+EAN10) y (CQ20+EAN20) resultaron igual de efectivas que la CQ20 de forma individual, para disminuir la parasitemia y aumentar la sobrevivencia de los animales infectados con Plasmodium berghei, lo que sugiere que el EAN no posee actividad antimalárica ni potencia el efecto de la CQ.

Optimized reaction conditions are developed to obtain a series of [(7-chloroquinolin-4-yl)sulfanyl] alcohol derivatives as intermediates to prepare a range of (7-chloroquinolin-4-ylthio) alkylbenzoate derivatives. The structures of all the synthesized compounds are confirmed from their infrared and nuclear magnetic resonance spectral data, and by elemental analysis. In silico ADME/Tox profiling studies of the synthesized molecules are undertaken, and the potential antimalarial activity of the products is determined. In vitro, all the prepared compounds significantly reduce heme crystallization with IC 50 values of < 10 µM. In vivo, the reduction in parasitemia levels and survival time increases are marginal.

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 β-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.

The β-hematin formation is a unique process adopted by Plasmodium sp. to detoxify free heme and represents a validated target to design new effective antimalarials. Most of the β-hematin inhibitors are mainly based on 4-aminoquinolines, but the parasite has developed diverse defense mechanisms against this type of chemical system. Thus, the identification of other molecular chemical entities targeting the β-hematin formation pathway is highly needed to evade resistance mechanisms associated with 4-aminoquinolines. Herein, we showed that the highly coordinative character can be a useful tool for the rational design of antimalarial agents targeting β-hematin crystallization. From a small library consisting of five compound families with recognized antitrypanosomatid activity and coordinative abilities, a group of tetradentate 1,4-disubstituted phthalazin-aryl/heteroarylhydrazinyl derivatives were identified as potential antimalarials. They showed a remarkable curative response against Plasmodium berghei-infected mice with a significant reduction of the parasitemia, which was well correlated with their good inhibitory activities on β-hematin crystallization (IC50 = 5–7 μM). Their in vitro inhibitory and in vivo responses were comparable to those found for a chloroquine reference. The active compounds showed moderate in vitro toxicity against peritoneal macrophages, a low hemolysis response, and a good in silico ADME profile, identifying compound 2f as a promising antimalarial agent for further experiments. Other less coordinative fused heterocycles exhibited moderate inhibitory responses toward β-hematin crystallization and modest efficacy against the in vivo model. The complexation ability of the ligands with iron(III) was experimentally and theoretically determined, finding, in general, a good correlation between the complexation ability of the ligand and the inhibitory activity toward β-hematin crystallization. These findings open new perspectives toward the rational design of antimalarial β-hematin inhibitors based on the coordinative character as an alternative to the conventional β-hematin inhibitors.

The synthesis of five new ( S)-methyl-(7-chloroquinolin-4-ylthio)acetamidoalquilate derivatives is carried out under a modified version of the Steglich esterification reaction between different l-amino acid methyl esters and 2-(7-chloroquinolin-4-ylthio)acetic acid. Two of the compounds showed significant inhibition (>50%) of β-hematin formation. The two active structures were tested in vivo as potential antimalarials in mice infected with Plasmodium berghei ANKA, a chloroquine susceptible strain. Compounds 6b and 6e exhibited antimalarial activity comparable to that of chloroquine.

The making of antibodies in animals can be demanding due to that several antigens, mostly of low molecular masses, provoke imperceptible immune response or are even totally nonimmunogenic. The transformation of non-immunogenic molecules into effective antigens represent an important immunological tasks. The crotamine from the rattlesnake Crotalus durissus cumanensis snake venom was purified by a Mono S HR 10/10 chromatography column and used to immunise C57/B mice, after to be polymerised with glutaraldehyde. The murine polyclonal antibodies directed against native crotamine-like (NCL) treated with glutaraldehyde and their product crotamine-like polymer (CLP) were generated by immunisation injecting CLP via lymph node cells. These antibodies were capable of detecting CLP in an enzyme-linked immunosorbent assay. The SDS-PAGE of NCL and CLP showed bands of molecular masses similar to 3 kDa and similar to 18 kDa, respectively. These results offer evidence that the polyclonal antibodies recognise specific putative original and post-polymerisation epitopes on the CLP molecule, which were maintained following the process of polymerisation. The results are discussed in relation to the preservation of a functional post-polymerisation epitopes on CLP.

A series of quinoline-chalcone (E)-1-[3 or 4-(7-chloroquinolin-4-ylamino) phenyl]-3-(phenyl substituted) prop-2-ene-1-one (4, 5), and quinoline-pyrazoline hybrids 7-Chloro-N-[3 or 4-(4,5-dihydro-5-(phenyl-substituted)-1H-pyrazol-3-yl] phenyl) quinoline-4–amine (6, 7) were synthesized with the aim of achieving an antimalarial and anticancer dual action. Most of the compounds showed significant inhibition (%>80) of β-hematin formation. The existing structures were tested in vivo as potential antimalarials in mice infected with P. berghei ANKA, chloroquine susceptible strain. Some of the compounds exhibited antimalarial activity comparable to that of chloroquine. Moreover, the compounds induce cell death on two human cancer cell lines (Jurkat E6.1 and HL60) without affecting the primary culture of human lymphocytes. Flow cytometry analysis confirmed the increase in apoptotic cell death after 24 h. Based on the structural analysis, these quinoline hybrids represent new compounds potentially useful for malaria end leukemia treatments.

The synthesis of the compounds [(7-chloroquinolin-4-yl)amino]acetophenones (4, 5) and their copper(II) complexes (4a, 5a) is reported. The compounds were characterized using a wide range of spectroscopic and spectrometric techniques, such as FTIR, UV-vis, NMR, EPR, ESI-CID-MS2. The spectral results suggested that the ligand acted as chelating species coordinating the metal through the endocyclic nitrogen of the quinoline ring in both complexes, with general formulae expressed in two ways, according to the phase in which they are: [Cu(L)2Cl2] for solid phase and [Cu(L)2][2Cl] for liquid phase. The EPR study of the Cu (II) complexes indicated a probable distorted tetrahedral coordination geometry. This result was confirmed by the calculated optimized structures at the DFT/B3LYP method with the 6-31G (d,p) basis set. The characterization of the fragmentation pattern of protonated free ligands was extended here to fragments as low as m/z 43, while for coordination complexes it extends to fragments at m/z 80 and m/z 111. The antimalarial activity of the compounds was determined through three different tests: inhibitory activity against in vitro growth of Plasmodium falciparum (W2), inhibition of hemozoin formation (β-hematin) and in vitro inhibitory activity against recombinant falcipain-2, where compound 5 showed considerable activity. However, the activity of free ligands against P. falciparum was increased by complexing with the Cu (II) metal ion. The values of the HOMO-LUMO energy gap of 3.847 eV (4a) and 3.932 eV (5a) were interpreted with high chemical activity and thus, could influence on biological activity. In both compounds, the total electron density surface mapped with electrostatic potential clearly revealed the presence of high negative charge on the Cu atom. Also, this study reported the molecular docking of free ligands (4, 5) using software package ArgusLab 4.0.1. The results revealed the importance of water molecules as interaction bridges through hydrogen bonds between free ligands and β-hematin; at the same time, the hypothesis that π-π interaction between quinoline derivatives and the electronic system of hematin governs the formation of adducts was confirmed.

Twenty-eight compounds of the type N´-substituted-2-(5-nitroheterocyclic-2-yl)-3H-benzo[d]imidazole-5-carboxamide were obtained using as an oxidizing agent the nitrobenzene to obtain the benzimidazole scaffold, a modification of the Steglich esterification reaction was used to obtain the final compounds. The compounds were tested as potential inhibitors of the β-hematin formation in vitro, and in vivo were tested as antimalarial against mice infected by a strain of Plasmodium berghei ANKA sensitive to chloroquine. The survival time was increased by the compounds 3a and 4d to 17.00 ± 1.26 and 20.20 ± 1.95 days, while the progress of the infection was reduced to 4.02 ± 0.45 and 3.05 ± 0.09, respectively. The cytotoxic activity of all these compounds was assessed against Jurkat E6.1 and HL60 two human cancer cell line, and fresh human lymphocytes. Four compounds 4a, n and 5a, n showed enhanced cytotoxicity against Jurkat E6.1 and HL60 cell lines; fresh lymphocytes were not affected. Using flow cytometry, apoptotic cell death was observed at 24 h. The aforementioned compounds enhanced apoptosis both tumor cell lines decreasing cell survival by inhibiting autophagy.

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 beta-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. (C) 2018 Elsevier Ltd. All rights reserved.

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.

The antirnalarial activity of sixteen ent-kaurenes was assayed on male albino mice infected with Plasmodium berghei. Ent-kaur-16-en-19-oic acid (kaurenic acid), l5iα-hydroxy- ent-kaur-16-en-19-oic acid, 15α-acetoxy- ent-kaur-16-en-19-oic acid, and ent-kaur-9(11)16-en-19-oic acid, natural kaurenes isolated from two species of Espelletiinae, were modified by semisynthesis to obtain methyl esters, glucopyranosyl esters, epoxides, 17-hydroxy, and isokaurenes (compounds with a 15,16-double bond). The kaurenes were first submitted to an in vitro test to measure their capacity to inhibit the formation of β-hematin. Compared with chloroquine (95.7%), the best effect was shown by 16,17-epoxy-ent-kauran-19-oic acid α-D- glucopyranosyl ester (2a), which produced 92.6% inhibition. Three other kaurenes showed good inhibition levels: ent-kaur- 16-en-I 9-oic acid (1a, 73.5%), 17-hydroxy- ent-kaur- I5-en-19-oic acid methyl ester (3b, 76.5%), and 15-oxo-16,17-epoxy-ent-kaur-16-en-19-oic acid (X-D-glucopyranosyl ester (4b,76.1%). These four compounds were assayed in a four day suppressive test in vivo (Peters' test) using chloroquine as a positive control. Two hours after infection the mice received the first treatment and then every 24 hours during four consecutive days. Blood smears from the tails were prepared on the fourth day and parasitemia was determined microscopically. Survivals were followed up to the 30th day post-infection, Once again compound 2a performed best, showing 4.5% of parasitemia on the fourth day post-infection (chloroquine 0.2%) and a survival time of 25.5 days (chloroquine 29.5 days; la 18.8 days, 4b 12.7 days and 3b 10.3 days). A comparative examination of the effect of all compounds on the in vitro test permitted the inference that the presence of a C- 19 carboxylic moiety was a requirement for the antimalarial activity and that a 16,17 epoxy group enhanced such activity.

Several trans- and cis-2-acetyl-3-(substituted-phenyl)-3,3a,4,5-tetrahydro-2 H-benzo[ g]indazole derivatives have been synthesised via the condensation of the appropriate exocyclic α,β-unsaturated ketones with hydrazine in hot acetic acid, to obtain diastereomeric mixtures of N-acetylated isomers. Structure elucidation was based on their spectral data and the trans–cis stereochemistry using of NOE and NOESY experiments. Biological testing of these derivatives as inhibitors of β-hematin formation was carried out.

Twelve 13-benzyl-15,16-bisnorlabdanes in which the C-13 and C-14 substituents are varied have been prepared from the naturally occurring labdane diterpene (+)-manool. These synthesised compounds were evaluated for antimalarial activity, in vitro as hemozoin formation inhibitors and in vivo against Plasmodium berghei. These derivatives were also assayed for antileishmanial activity against Leishmania mexicana.

Some novel derivatives of Bis-chalcone were synthesized and characterized by their physical and spectral data. All the synthesized compounds were subsequently screened for in vitro globin hydrolysis, beta-hematin formation, and murine Plasmodium berghei, using chloroquine as the reference drug. Most of the synthesized compounds exhibited mild to moderate susceptibilities toward the parasite in comparison with the standard. The most active antimalarial compound was 1,1-Bis-[(3',4'-N-(urenylphenyl)-3-(3 '',4 '',5 ''-trimethoxyphenyl)]-2-propen-1-one 5, with a percentage of inhibition of heme polymerization of 87.05 +/- 0.77, and this compound increased the survival time after infection, reduce the parasitemia and delay the progression of malaria.

la cloroquina y la quinina han sido los antimalaricos mas usados durante las ultimas decadas, no obstante, la resistenciaque ha desarrollado el Plasmodium en contra de la primera y la toxicidad de la segunda, han limitado su uso.por ello, en la actualidad hay una imperiosa necesidad de desarrollar nuevos medicamentos para combatir la malaria.En este estudio fue sintetizado un grupo de pirazoloquinolinas como potenciales inhibidores de la formacion dela hemozoina, el cual es un mecanismo de defensa utilizado por el parasito para evitar los efectos toxicos del hemo.En ensayos in vitro, los compuestos 17 y 11b inhibieron la formacion de hemozoina en un 85% y un 79%, respectivamente,mientras que cloroquina tuvo una inhibicion del 88%. En las evaluaciones in vivo, prueba de peter, 11bredujo la parasitemia al 8% mientras que cloroquina la redujo al 4% en el mismo ensayo.