Exploring the antileishmanial activity of N1,N2-disubstituted-benzoylguanidines: synthesis and molecular modeling studies (original) (raw)
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Bioorganic & Medicinal Chemistry, 2004
In order to optimize the antileishmanial activity of piperazinyl-linked 5-(5-nitrofuran-2-yl)-1,3,4-thiadiazoles, we synthesized a series of 5-(5-nitrofuran-2-y1)-1,3,4-thiadiazoles with piperazinyl-linked benzamidine substituent as scaffold found in pentamidine related antiprotozoals. The structure of target compounds was confirmed by IR, 1 H NMR, 13 C NMR and Mass spectral data. All compounds were tested for in vitro activity against the promastigote and amastigote forms of Leishmania major. From the results, we found that the substitution on amidine nitrogen has profound role in the biological activity of these compounds. The 5-nitrofuran-2-yl-1,3,4-thiadiazoles having n-propyl, n-butyl and benzyl side chain on benzamidine (as in compounds 2d, 2e and 2g, respectively) showed very good activity in both forms of promastigote and amastigote. The most active compound was N-propyl-4-(4-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-yl)piperazin-1-yl) benzamidine hydrochloride (2d) with IC 50 value of 0.08 mM in promastigote model. This compound showed a very low level of toxicity against macrophages (CC 50 ¼ 785 mM), with the highest selectivity index (SI ¼ 78.5) among the tested compounds.
Antimicrobial Agents and Chemotherapy, 2014
We investigated the in vitro effects of four alkyl-galactofuranoside derivatives, i.e. octyl-β-D-31 galactofuranoside (1), 6-amino-β-D-galactofuranoside (2), 6-N-acetamido-β-D-galactofuranoside 32 (3), and 6-azido-β-D-galactofuranoside (4) on Leishmania donovani. Their mechanism of action was 33 explored using electron paramagnetic resonance spectroscopy (EPR) and nuclear magnetic resonance 34 (NMR), and ultrastructural alterations by transmission electron microscopy (TEM). Compound 1 35 showed the most promising effects by inhibiting promastigote growth at IC 50 8.96 ± 2.5 µM. All 36 compounds exhibit low toxicity towards human macrophages. Compound 1 had a higher selectivity 37 index than the comparative molecule used, i.e. miltefosine (159.7 versus 37.9, respectively). EPR 38 showed that compound 1 significantly reduced membrane fluidity, compared to control 39 promastigotes and to compound 3. The furanose ring was shown to support this effect since the 40 isomer galactopyranose had no effect on parasite membrane fluidity or growth. NMR showed a 41 direct interaction of all compounds (1>2>3>4) with the promastigote membrane, as well as with 42 octyl-galactopyranose and octanol, providing evidence that the n-octyl chain was primarily involved 43 in the anchoring with the parasite membrane, followed by the putative crucial role of furanose ring in 44 the anti-leishmanial activity. A morphologic analysis of compound 1-treated promastigotes by TEM 45 revealed profound alterations on parasite membrane and organelles, but not with compound 3. 46 Quantification of annexinV binding by flow cytometry confirmed that compound 1 induced 47 apoptosis in >90% promastigotes. The effect of compound 1 was also assessed on intra-macrophagic 48 amastigotes, and showed a reduction in amastigote growth associated with an increase of ROS 49 production, thus validating its promising effect. 50 51 101 6 cleavage of the ester groups of 3b gave 3 in 30% yields starting from 4b. In parallel, direct 102 deprotection of the benzoyl protecting groups of 4b under basic conditions provided the free octyl 6-103 azido-galactofuranoside 4. Details about the synthesis could be provided upon request. The four 104 resulting products, namely octyl β-D-galactofuranoside 1, 6-amino-galactofuranoside 2, 6-N-105 acetamido-β-D-galactofuranoside 3 and 6-azido-galactofuranoside 4, were then tested (19). In some 106 experiments, two other compounds were used as controls, i.e. octyl-β-D-galactopyranoside 5 (Galp-107 Oct) and octanol 6 (FIG.1). Miltefosine (hexadecylphosphocholine [HePC]) was used as reference 108 molecule with proven efficacy against visceral leishmaniasis (20). ) as 114 MHOM/SD/97/LEM3427, Zym MON-18. Schneider's drosophila medium (Sigma-Aldrich) 115 supplemented with 10% fetal calf serum (FCS) (InVitrogen) was used to amplify parasites from 116 amastigotes freshly isolated from mice, and to maintain the serial passages of L. donovani 117 promastigotes at 27°C. L. donovani cultures at 3-5 days (exponential growth phase) were used to 118 determine the anti-parasitic effect of the different derivatives of galactofuranose. For cell infection 119 experiments, promastigote cultures at stationary phase were used.
2 Synthesis Cytotoxicity Antibacterial and Antileishmanial Activities of
This paper describes the synthesis and in vitro biological activities of imidazolidine and hexahydropyrimidine derivatives against bacteria (Escherichia coli, Staphylococcus aureus and Mycobacterium tuberculosis) and Leishmania protozoa. Out of sixteen heterocyclic derivatives tested, none were cytotoxic against mammalian cells. The compounds showed significant bacterial effects and leishmanicidal activity. Compounds 4a and 4c were active against S. aureus and E. coli, respectively. Compounds 3a-3f, 4h and 4i presented promising results against M. tuberculosis, with MIC values ranging from 12.5 to 25.0 g/mL, comparable to the "first and second line" drugs used to treat tuberculosis. Compounds 4a, 4c and 4e were active against L major. Three of them were structurally characterized by single-crystal X-ray diffraction.
Journal of Antimicrobial Chemotherapy, 2002
Current therapies for Chagas' disease, leishmaniasis and tuberculosis are unsatisfactory because of the failure rates, significant toxicity and/or drug resistance. In this study, the compound 3-[4′-bromo-(1,1′-biphenyl)-4-yl]-N,N-dimethyl-3-(2-thienyl)-2-propen-1-amine (IV) was synthesized and its trypanocidal, leishmanicidal and antimycobacterial activities were investigated. The cytotoxicity was determined on V79 cells with three endpoints: nucleic acid content, 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide reduction and Neutral Red uptake. This compound was active against different species of mycobacteria and different life cycle stages of Trypanosoma cruzi. In experiments with trypomastigotes performed at 4°C in the presence of blood, the activity was 8.8-fold more active than the standard drug, Crystal Violet. Higher activity was achieved against Leishmania amazonensis, with an ED 50 /24 h of 3.0 ± 0.3 µmol/L. The effect against trypanosomatids, which suggests high activity of compound IV against promastigotes of L. amazonensis and amastigotes of T. cruzi, stimulated further studies in vitro with amastigotes interiorized in macrophages and with in vivo models. Our results indicate that mammalian V79 cells are less susceptible to the action of compound IV than promastigotes of L. amazonensis (8.0-13.3-fold) and axenic amastigotes of T. cruzi (3.5-5.9-fold).
Acta tropica, 2018
The present study evaluates in vitro the effect of two synthetic compounds of the 7-chloro-4-aryloxyquinoline series, QI (CHClNO) and QII (CHClNOS), on Leishmania donovani parasites. The results obtained demonstrate that these compounds are able to inhibit the proliferation of L. donovani promastigotes in a dose-dependent way (QI IC = 13.03 ± 3.4 and QII IC = 7.90 ± 0.6 μM). Likewise, these compounds significantly reduced the percentage of macrophage infection by amastigotesand the number of amastigotes within macrophage phagolysosomes, the clinical relevant phase of these parasites. Compound QI showed an IC value of 0.66 ± 0.2 μM, while for derivative QII, the corresponding IC was 1.02 ± 0.17 μM. Interestingly, the amastigotes were more susceptible to the drug treatment when compared to promastigotes. Furthermore, no cytotoxic effect of these compounds was observed on the macrophage cell line at the concentrations tested. The combination of these compounds with miltefosine and amph...
Journal of Natural Products, 2016
Synthetic analogues of marine sponge guanidine alkaloids showed in vitro antiparasitic activity against Leishmania (L.) infantum and Trypanosoma cruzi. Guanidines 10 and 11 presented the highest selectivity index when tested against Leishmania. The antiparasitic activity of 10 and 11 was investigated in host cells and in parasites. Both compounds induced depolarization of mitochondrial membrane potential, upregulation of reactive oxygen species levels, and increased plasma membrane permeability in Leishmania parasites. Immunomodulatory assays suggested an NO-independent effect of guanidines 10 and 11 on macrophages. The same compounds also promoted anti-inflammatory activity in L. (L.) infantum-infected macrophages cocultived with splenocytes, reducing the production of cytokines MCP-1 and IFN-γ. Guanidines 10 and 11 affect the bioenergetic metabolism of Leishmania, with selective elimination of parasites via a hostindependent mechanism.
Some novel antileishmanial compounds inhibit normal cell cycle progression of Leishmania donovani promastigotes and exhibits pro-oxidative potential, 2021
In the midst of numerous setbacks that beclouds the fight against leishmaniasis; a neglected tropical disease, the search for new chemotherapeutics against this disease is of utmost importance. Leishmaniasis is a disease closely associated with poverty and endemic in Africa, Asia, southern Europe and the Americas. It is caused by parasites of the genus Leishmania and transmitted by a sandfly vector. In this study, we evaluated the antileishmanial potency of eighteen pathogen box compounds and elucidated their biosafety and possible mechanisms of action against Leishmania donovani promastigotes and amastigotes in vitro. IC 50 s range of 0.12±0.15 to >6.25 μg/ml and 0.13±0.004 to >6.25μg/ml were observed for the promastigotes and amastigotes, respectively. We demonstrated the ability of some of the compounds to cause cytocidal effect on the parasites, induce increased production of reactive oxygen species (ROS), disrupt the normal parasite morphology and cause the accumulation of parasites at the DNA synthesis phase of the cell cycle. We recommend a further in vivo study on these compounds to validate the findings.
Bioscience Journal
Leishmaniasis are a group of parasitic zoonoses provoked by protozoa from Leishmania genus and belonging to the group of neglected tropical diseases. The search and development for new drugs is necessary not only to investigate the activity against only the parasite, but also to investigate the possible synergistic effect of new drugs with the immune response of the host. In the present review, macrophages are pointed out as potential targets of the investigation of new antileishmanial drugs, and some methodologies in order to assess their activation as response to Leishmania-infected cells are presented. Macrophages are an important role in the cellular immune response, since they are cells from mononuclear phagocytic system, the first line of defense of the host, against parasites from Leishmania genus. Phagocytic capacity, lysosomal activity, increase of nitric oxide and intracellular calcium levels are parameters regarding assessment of macrophages activation which allow them to...
Action of new organometallic complexes against Leishmania donovani
Journal of Antimicrobial Chemotherapy, 1997
The action of 16 newly synthesized metal complexes having the general structure cis-Pt-(II)-X n-L n have been tested in vitro against the promastigote forms of Leishmania donovani. The metal complexes at 24 h and maximum dosages inhibited growth from 0%, e.g. in cis-Ptnifurtimox, to 100%, e.g. in cis-Pt-(2,3,4,5,6-pentafluoroaniline) 2 Br 2 or cis-Pt-pentamidine-I 2. A study of the cytotoxicty of these latter complexes on the phagocytic cell line J-774 showed neither high cytotoxicity nor cytolysis. At the maximum dosage after 24 h of permanent contact with the cells (extreme, non-physiological conditions), cytolysis did not exceed 30%. For most of the compounds, cytolysis ranged from 0%, for cis-Pt-oxamniquine-Cl 2 to 27.7%, for cis-Pt-pentamidine-I 2. The compound cis-Pt-(2,3,4,5,6-pentafluoroaniline) 2-Br 2 caused up to 1.4% cytolysis under the above conditions. Parasites exposed to cis-Pt-pentamidine-I 2 showed notably reduced DNA, RNA and protein synthesis, unlike those exposed to other compounds. Parasites examined by electron microscopy showed effects mainly on the nucleus, though in some cases the mitochondria were affected, altering the internal membranes of the cytoplasmic organelles. The in-vivo activity of the complex cis-Pt-guanethidine-Cl 2 was evaluated in parasitized Wistar rats, in which the number of amastigotes per gram of spleen was reduced by 75% compared with controls.