Antiprotozoal activities of symmetrical bishydroxamic acids (original) (raw)
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Anti-Leishmanial activity of homo- and heteroleptic bismuth(III) carboxylates
Journal of Inorganic Biochemistry, 2011
a b s t r a c t Bismuth(III) complexes of NSAIDs (Non-Steroidal Anti Inflammatory Drugs) and substituted benzoic acids (omethoxybenzoic acid, m-methoxybenzoic acid, o-nitrobenzoic acid, 3,5-diacetamidobenzoic acid, and 5-[(R/S)-2,3-dihydroxypropyl carbamoyl]-2-pyridine carboxylic acid) have been synthesised and fully characterised. Two new bis-carboxylato bismuth complexes have been characterised by single crystal X-ray diffraction, namely [PhBi (o-MeOC 6 H 4 CO 2 ) 2 (bipy)]·0.5EtOH (bipy = 2,2'-bipyridine) and [PhBi(C 9 H 11 N 2 O 3 CO 2 ) 2 (H 2 O)]·6H 2 O. All compounds were tested against the parasite Leishmania major promastigotes for their anti-Leishmanial activity and were further assessed for their toxicity to mammalian cells. The NSAID free acids and their bismuth derivatives show negligible anti-Leishmanial activity at concentrations 1.95 to 250 μg/mL against the promastigotes of L. major whereas in the case of mammalian cells only bismuth complexes of naproxen and mefenamic acid have significant effect at concentration ≥ 250 μg/mL. The bismuth(III) complexes of substituted benzoic acids show significant anti-Leishmanial activity against the promastigotes of L. major V121 at very low concentrations while their respective free carboxylic acids show no effective activity. However, the bismuth compounds inhibit the growth of the mammalian cells at all concentrations studied (1.95 to 500 μg/mL) following 48 h incubation. The comparatively low toxicity of BiCl 3 and Bi(NO 3 ) 3 , suggests that overall toxicity of bismuth complexes towards the parasite is both ligand and metal dependent.
Bis(oxyphenylene)benzimidazoles: A novel class of anti-Plasmodium falciparum agents
Bioorganic & Medicinal Chemistry, 2011
A small library of 26 2,2 0 -[alkane-a,x-diylbis(oxyphenylene)]bis-1H-benzimidazoles has been prepared and evaluated against Giardia intestinalis, Entamoeba histolytica, Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum. Among the tested compounds, eight derivatives and 35) exhibited an anti-Plasmodium falciparum activity characterized by IC 50 values in the range of 180-410 nM (0.11-0.21 lg/mL) and selectivity indexes (IC 50 rat skeletal myoblasts L6 cells vs IC 50 P. falciparum K1 strain) varying between 92 and more than 450. Two of the eight novel drug leads, namely compounds 19 and 32, were also active against G. intestinalis and L. donovani with selectivity indexes of 122 and >164 respectively.
European Journal of Medicinal Chemistry, 2017
Malaria is one of the most significant tropical diseases and remains a major challenge due to the lack of a broadly effective vaccine and parasite resistance to current drugs. This means there is a need for new drug candidates with novel modes of action. Aromatic bisamidines, such as furamidine (DB75), were initially developed as anti-Trypanosoma agents however as clinical trials with furamidine highlighted potential side effects they were not pursued further in that setting. Despite apparent cytotoxicity liabilities the potency of furamidine against Plasmodium falciparum makes it a promising scaffold for the development of new anti-Plasmodium agents with improved selectivity. In this study a bisamidine compound series based on furamidine was synthesized by introducing modifications at the furan core structure and terminal amidine groups. The activity of the derived compounds was tested in vitro against drug sensitive and resistant P. falciparum lines and a human cell line (HEK293 cells) to generate anti-Plasmodium structure-activity relationships and to provide preliminary selectivity data.
Bioorganic & Medicinal Chemistry, 2009
Here, we describe a series of readily obtainable benzophenone derivatives with antimalarial and antitrypanosomal activity. The most active compounds display submicromolar activity against Plasmodium falciparum. Micromolar activity is obtained against Trypanosoma brucei. Main problem of the compounds is low selectivity. However, there are indications that separation of antimalarial and cytotoxic activity might by possible. In addition, some compounds inhibit human ABC transporter with nanomolar activity.
New antimalarial agents derived from nonlinear phenoxazine ring system
Medicinal Chemistry Research, 2019
In vivo antimalarial screening of nine nonlinear phenoxazine compounds was carried out on the blood stages of Plasmodium berghei using standard methods. The activities of the compounds were compared with that of quinine as a standard antimalarial drug. LD 50 and histopathological studies were also done. Molecular docking studies were carried out on four different protein targets of Plasmodium spp. The effects of these compounds on the hematological parameters (Hemoglobin, Hb; packed cell volume, PCV; white blood cells, WBC; and red blood cells, RBC) were also evaluated. The in vivo antimalarial studies showed that all the synthesized compounds had significant parasitaemia load reduction (89.00-94.05%) at 200 mg/ml when compared with the control, with (2-aminophenoxyl)benzo[a]phenoxazin-5-one 3b showing the highest activity. There was no significant difference in the activities of these compounds compared with the standard drug used (96%). The LD 50 was found to be ≥5000 mg/kg. Histopathological studies showed a significant restoration of the liver intoxicated with malaria parasite after 5 days. The hematological analysis showed normal values for Hb, PCV, WBC, and RBC in the course of the treatment. The compounds showed more binding affinities for the P. falciparum receptors than the standard drug. The nine synthesized nonliner phenoxazine compounds had significant antimalarial activities and did not significantly affect the hematological parameters. They showed strong binding affinity to the parasite receptors. Hence, they are good candidates for antimalarial drugs. More preclinical investigations are needed.
Journal of Medicinal Chemistry, 2000
Forty bis(9-amino-6-chloro-2-methoxyacridines), in which acridine moieties are joined by alkanediamines, polyamines, or polyamines substituted by a side chain, were synthesized and tested for their in vitro activity upon the erythrocytic stage of Plasmodium falciparum, trypomastigote stage of Trypanosoma brucei, and amastigote stage of Trypanosoma cruzi and Leishmania infantum as well as for their cytotoxic effects upon MRC-5 cells. Results clearly showed the importance of the nature of the linker and of its side chain for antiparasitic activity, cytotoxicity, and cellular localization. Among several compounds devoid of cytotoxic effects at 25 µM upon MRC-5 cells, one displayed IC 50 values ranging from 8 to 18 nM against different P. falciparum strains while three others totally inhibited T. brucei at 1.56 µM. # Abbreviations: CQ, chloroquine; DAPI, 4,6-diamidino-2-phenylindole; MF, mefloquine; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (thiazolyl blue); PyBrop, bromotris(pyrrolidinophosphonium) hexafluorophosphate. . Labeling of T. cruzi epimastigotes with compound 9: A, phase contrast; B, labeling with 1 µM compound 9. Fluorescence was mainly associated with a structure which colocalized with kinetoplast DNA (K). Bar ) 3 µm.
Antimalarial Activities of Polyhydroxyphenyl and Hydroxamic Acid Derivatives
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Journal of Chemical Research, 2013
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.
Antimalarial activity of 3-hydroxyalkyl-2-methylene-propionic acid derivatives
Bioorganic & Medicinal Chemistry Letters, 1999
Several Baylis-Hillmau adducts and their derivatives were synthesized and evaluated as targeted potential anti-malarials. The compounds 4, 7 and 9 were found to have highest potency against P. falciparum in vitro. The m vivo test result of compound 4 and 9 against P. berghei demonstrated activity at 80 mg/Kg dose level.