Standard Drug Pentamidine Research Articles

Structure-Activity Study on Substituted, Core-Extended, and Dyad Naphthalene Diimide G-Quadruplex Ligands Leading to Potent Antitrypanosomal Agents.

Several G-quadruplex nucleic acid (G4s) ligands have been developed seeking target selectivity in the past decade. Naphthalene diimide (NDI)-based compounds are particularly promising due to their biological activity and red-fluorescence emission. Previously, we demonstrated the existence of G4s in the promoter region of parasite genomes, assessing the effectiveness of NDI-derivatives against them. Here, we explored the biological activity of a small library of G4-DNA ligands, exploiting the NDI pharmacophore, against both Trypanosoma brucei and Leishmania major parasites. Biophysical and biological assays were conducted. Among the various families analyzed, core-extended NDIs exhibited the most promising results concerning the selectivity and antiparasitic effects. NDI 16 emerged as the most potent, with an IC50 of 0.011 nM against T. brucei and remarkable selectivity vs MRC-5 cells (3454-fold). Fascinating, 16 is 480-fold more potent than the standard drug pentamidine (IC50 = 5.3 nM). Cellular uptake and parasite localization were verified by exploiting core-extended NDI red-fluorescent emission.

Anti-Leishmanial and Cytotoxic Activities of a Series of Maleimides: Synthesis, Biological Evaluation and Structure-Activity Relationship.

In the present study, 45 maleimides have been synthesized and evaluated for anti-leishmanial activities against L. donovani in vitro and cytotoxicity toward THP1 cells. All compounds exhibited obvious anti-leishmanial activities. Among the tested compounds, there were 10 maleimides with superior anti-leishmanial activities to standard drug amphotericin B, and 32 maleimides with superior anti-leishmanial activities to standard drug pentamidine, especially compounds 16 (IC50 < 0.0128 μg/mL) and 42 (IC50 < 0.0128 μg/mL), which showed extraordinary efficacy in an in vitro test and low cytotoxicities (CC50 > 10 μg/mL). The anti-leishmanial activities of 16 and 42 were 10 times better than that of amphotericin B. The structure and activity relationship (SAR) studies revealed that 3,4-non-substituted maleimides displayed the strongest anti-leishmanial activities compared to those for 3-methyl-maleimides and 3,4-dichloro-maleimides. 3,4-dichloro-maleimides were the least cytotoxic compared to 3-methyl-maleimides and 3,4-non-substituted maleimides. The results show that several of the reported compounds are promising leads for potential anti-leishmanial drug development.

Synthesis of Thiocarbohydrazones and Evaluation of their in vitro Antileishmanial Activity.

Leishmaniasis is a protozoan parasitic vector-borne disease which is endemic in 88 tropical countries. Infected sandfly is the main vector of this disease, while there are several other vectors, parasites, and reservoirs involved in the transmission of this disease. Leishmania donovani, L. infantum, and L. chagasi are common disease causing species, transmitted through sandflies. Leishmaniasis is a neglected tropical disease with broad spectrum of clinical manifestations. Cutaneous leishmaniasis is prevalent in many countries, including Pakistan. Thiocarbohydrazones (1-20) were synthesized through one pot method by refluxing thiocarbahydrazide with different substituted benzaldehydes in ethanol in the presence of acetic acid as a catalyst. These synthetic compounds were evaluated for their potential antileishmanial activity in vitro against Leishmania major promastigotes. Compounds 5-8, 11, 14, 16, 17, 19 and 20 were reported earlier, while compounds 2-4, 9, 10, 12, 13 and 15 were identified as were derivatives. Compounds 1-20 demonstrated antileishmanial activities with IC50 values between 1.63 ± 0.05 - 64.82 ± 0.17 µM, as compared to the standard drug pentamidine (IC50 = 5.09 ± 0.04 µM). Compounds 2 (IC50 = 1.63 ± 0.05 µM), 11 (IC50 = 2.33 ± 0.01 µM), 4 (IC50 = 11.03 ± 0.20 µM), and 10 (IC50 = 11.63 ± 0.06 µM) displayed comparable antileishmanial activities to the standard drug pentamidine. However, compounds 13, 15-17, and 20 with IC50 values 36.95 ± 0.025, 64.82 ± 0.17, 64.27 ± 0.38, 62.34 ± 0.38, and 40.47 ± 0.05 µM, respectively, showed a moderate antileishmanial activity. In contrast, compounds 1, 3, 5-9, 12, 14, 18, and 19 demonstrated less than 50% growth inhibition of promestigotes of L. major, and thus considered as inactive. In thiocarbohydrazone derivatives, different substituents at aryl part may be responsible for a varying degree of antileishmanial activity in vitro. Consequently, these compounds might have a potential for further studies as a new class of antileishmanial agents.

Synthesis and Biological Evaluation of 8-Quinolinamines and Their Amino Acid Conjugates as Broad-Spectrum Anti-infectives.

In the search of therapeutic agents for emerging drug-resistant parasites, the synthesis of newer classes of 8-quinolinamines has emerged as a successful chemotherapeutic approach. We report synthesis of 8-quinolinamines bearing 5-alkoxy, 4-methyl, and 2-tert-butyl groups in the quinoline framework and their amino acid conjugates as broad-spectrum anti-infectives. 8-Quinolinamines exhibited potent in vitro antimalarial activity [IC50 = 20–4760 ng/mL (drug-sensitive Plasmodium falciparum D6 strain) and IC50 = 22–4760 ng/mL (drug-resistant P. falciparum W2 strain)]. The most promising analogues have cured all animals at 25 mg/kg/day against drug-sensitive Plasmodium berghei and at 50 mg/kg/day against multidrug-resistant Plasmodium yoelii nigeriensis infections in Swiss mice. The in vitro antileishmanial activities (IC50 = 0.84–5.0 μg/mL and IC90 = 1.95–7.0 μg/mL) comparable to standard drug pentamidine were exhibited by several of the synthesized 8-quinolinamines. At the same time, very promising antifungal activities (Candida albicans—IC50 = 4.93–19.38 μg/mL; Candida glabrata—IC50 = 3.96–19.22 μg/mL; Candida krusei—IC50 = 2.89–18.95 μg/mL; Cryptococcus neoformans—IC50 = 0.67–18.64 μg/mL; and Aspergillus fumigatus—IC50 = 6.0–19.32 μg/mL) and antibacterial activities (Staphylococcus aureus—IC50 = 1.33–18.9 μg/mL; methicillin-resistant S. aureus—IC50 = 1.38–15.34 μg/mL; and Mycobacterium intracellulare—IC50 = 3.12–20 μg/mL) were also observed. None of the 8-quinolinamines exhibited cytotoxicity and therefore are a promising structural class of compounds as antiparasitic and antimicrobials.

New Polyisoprenylated Polycyclic Phloroglucines from Clusia gundlachii

A bioassay-guided fractionation yielded five new polycyclic phloroglucines derivatives, namely, gundlachiione A (1), gundlachiione B (2), gundlachiione C (3), gundlachiione D (4) and gundlachiione E (5) from the fruits of Clusia gundlachii, collected in Puerto Rico, USA. Their structures were determined by full spectroscopic data, including 2D NMR COSY, HMQC, HMBC, and NOESY experiments, and HRESIMS. Compounds 1 and 3 demonstrated activities against Leishmania donovani intracellular macrophage amastigotes in THP1 cultures, comparable to those observed for the standard drug pentamidine (IC50 and IC90 values 0.84 and 6.13 μg/mL, 2.32 and 3.01 μg/mL, 0.77 and 2.99 μg/mL, respectively). Both compounds, 1 and 3, also showed weak activities against L. donovani promastogotes and absence of cytotoxicity against transformed THP 1 cells.

Inhibitory effects of (+)-spectaline and iso-6-spectaline from Senna spectabilis on the growth and ultrastructure of human-infective species Trypanosoma brucei rhodesiense bloodstream form

In our ongoing work searching for new trypanocidal lead compounds from Malaysian plants, two known piperidine alkaloids (+)-spectaline (1) and iso-6-spectaline (2) were isolated from the leaves of Senna spectabilis (sin. Cassia spectabilis). Analysis of the 1H and 13C NMR spectra showed that 1 and 2 presented analytical and spectroscopic data in full agreement with those published in the literature. All compounds were screened in vitro against Trypanosoma brucei rhodesiense in comparison to the standard drug pentamidine. Compound 1 and 2 inhibited growth of T. b. rhodesiense with an IC50 value of 0.41 ± 0.01 μM and 0.71 ± 0.01 μM, without toxic effect on L6 cells with associated a selectivity index of 134.92 and 123.74, respectively. These data show that piperidine alkaloids constitute a class of natural products that feature a broad spectrum of biological activities, and are potential templates for the development of new trypanocidal drugs. To our knowledge, the compounds are being reported for the first time to have inhibitory effects on T. b. rhodesiense. The ultrastructural alterations in the trypanosome induced by 1 and 2, leading to programmed cell death were characterized using electron microscopy. These alterations include wrinkling of the trypanosome surface, formation of autophagic vacuoles, disorganization of kinetoplast, and swelling of the mitochondria. These findings evidence a possible autophagic cell death.

Evaluation of Chemical Composition and Antileishmanial and Antituberculosis Activities of Essential Oils of Piper Species.

Essential oils from fresh Piperaceae leaves were obtained by hydrodistillation and analyzed by gas chromatography mass spectrometry (GC–MS), and a total of 68 components were identified. Principal components analysis results showed a chemical variability between species, with sesquiterpene compounds predominating in the majority of species analyzed. The composition of the essential oil of Piper mosenii was described for the first time. The cytotoxicity of the essential oils was evaluated in peritoneal macrophages and the oils of P. rivinoides, P. arboretum, and P. aduncum exhibited the highest values, with cytotoxic concentration at 50% (CC50) > 200 µg/mL. Both P. diospyrifolium and P. aduncum displayed activity against Leishmania amazonensis, and were more selective for the parasite than for the macrophages, with a selectivity index (SI) of 2.35 and >5.52, respectively. These SI values were greater than the 1 for the standard drug pentamidine. The antileishmanial activity of the essential oils of P. diospyrifolium and P. aduncum was described for the first time. P. rivinoides, P. cernuum, and P. diospyrifolium displayed moderate activity against the Mycobacterium tuberculosis H37Rv bacillus, with a minimum inhibitory concentration (MIC) of 125 µg/mL. These results are relevant and suggests their potential for therapeutic purposes. Nevertheless, further studies are required to explain the exact mechanism of action of these essential oils.

Synthesis and molecular modelling studies of phenyl linked oxadiazole-phenylhydrazone hybrids as potent antileishmanial agents

Molecular hybridization yielded phenyl linked oxadiazole-benzohydrazones hybrids 6–35 and were evaluated for their antileishmanial potentials. Compound 10, a 3,4-dihydroxy analog with IC50 value of 0.95 ± 0.01 μM, was found to be the most potent antileishmanial agent (7 times more active) than the standard drug pentamidine (IC50 = 7.02 ± 0.09 μM). The current series 6–35 conceded in the identification of thirteen (13) potent antileishmanial compounds with the IC50 values ranging between 0.95 ± 0.01–78.6 ± 1.78 μM. Molecular docking analysis against pteridine reductase (PTR1) were also performed to probe the mode of action. Selectivity index showed that compounds with higher number of hydroxyl groups have low selectivity index. Theoretical stereochemical assignment was also done for certain derivatives by using density functional calculations.

Investigation into in vitro anti-leishmanial combinations of calcium channel blockers and current anti-leishmanial drugs

The need for drug combinations to treat visceral leishmaniasis (VL) arose because of resistance to antimonials, the toxicity of current treatments and the length of the course of therapy. Calcium channel blockers (CCBs) have shown anti-leishmanial activity; therefore their use in combination with standard drugs could provide new alternatives for the treatment of VL. In this work, in vitro isobolograms of Leishmania (Leishmania) chagasi using promastigotes or intracellular amastigotes were utilised to identify the interactions between five CCBs and the standard drugs pentamidine, amphotericin B and glucantime. The drug interactions were assessed with a fixed ratio isobologram method and the fractional inhibitory concentrations (FICs), sum of FICs (ΣFICs) and the overall mean ΣFIC were calculated for each combination. Graphical isobologram analysis showed that the combination of nimodipine and glucantime was the most promising in amastigotes with an overall mean ΣFIC value of 0.79. Interactions between CCBs and the anti-leishmanial drugs were classified as indifferent according to the overall mean ΣFIC and the isobologram graphic analysis.

Synthesis and biological evaluation of new [1,2,4]triazino[5,6- b]indol-3-ylthio-1,3,5-triazines and [1,2,4]triazino[5,6- b]indol-3-ylthio-pyrimidines against Leishmania donovani

A series of [1,2,4]triazino[5,6- b]indol-3-ylthio-1,3,5-triazines and [1,2,4]triazino[5,6- b]indol-3-ylthio-pyrimidines were synthesized and screened for their in vitro antileishmanial activity against Leishmania donovani. Among all, 8 compounds have shown more than 90% inhibition against promastigotes and IC 50 in the range of 4.01–57.78 μM against amastigotes. Compound 5, a triazino[5,6- b]indol-3-ylthio-1,3,5-triazine derivative was found to be the most active and least toxic with 20- & 10-fold more selectivity (S.I. = 56.61) as compared to that of standard drugs pentamidine and sodium stibogluconate (SSG), respectively.

Synthesis and in vitro activity of limonene derivatives against Leishmania and Trypanosoma

The synthesis and in vitro activity of R(+)-Limonene derivatives against Leishmania and Trypanosoma cruzi strains are reported. Seven compounds have shown better in vitro activity against Leishmania (V.)braziliensis than the standard drug pentamidine. Additionally, we have identified two promising new anti- T. cruzi limonene derivatives.

Isolation of antileishmanial sterol from the fruits of Cassia fistula using bioguided fractionation

Natural products represent a rich source of new chemical entities for the development of drugs for neglected diseases. Leishmaniasis still afflicts the poorest populations in the world, with 12 million cases worldwide. This work analysed crude extracts and fractions from the fruits of Cassia fistula against the most dramatic and fatal disease form of leishmaniasis, the visceral form (VL). Hexane extract from the fruits showed significant antileishmanial activity against the promastigote form of Leishmania L. chagasi. The bioguided fractionation resulted in the isolation of a sterol, clerosterol, which was further analysed in different models. Promastigotes presented an inhibitory concentration 50% (IC50) of 10.03 microg/mL and intracellular amastigotes demonstrated high susceptibility, with an IC50 of 18.10 microg/mL. Mammalian cytotoxicity was evaluated and it was demonstrated that clerosterol was 3.6-fold less toxic than the standard drug pentamidine. No antifungal activity of the isolated clerosterol was found. Future studies of the extracted compounds of Cassia fistula could be a useful tool for the development of new therapeutic agents for VL.

Synthesis, antimalarial, antileishmanial, and antimicrobial activities of some 8-quinolinamine analogues

In the present communication, newly synthesized 8-quinolinamines (25–27) related to previously reported 2-tert-butylprimaquine (2) were evaluated for their in vitro antimalarial activity against chloroquine sensitive and resistant Plasmodium falciparum strains, in vivo antimalarial activity against P. berghei infected mice, in vitro antileishmanial activity against Leishmania donovani, in vitro antimicrobial activity against various fungi and bacteria, and cytotoxicity in a panel of mammalian cell lines. No promising cytotoxicities were observed for compounds reported herein. Analogue 25 was found to exhibit curative antimalarial activity at a dose of 25mg/kg/day×4 in a P. berghei infected mice model, and produced suppressive activity at a lower dose of 10mg/kg/day×4. In vitro antileishmanial activities (IC50 and IC90) comparable to standard drug pentamidine were exhibited by all synthesized 8-quinolinamines 25–27. At the same time, promising antibacterial and antifungal activities were also observed for synthesized compounds against a panel consisting of several bacteria and fungi.

Activity of extracts and naphthoquinones from Kigelia pinnata against Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense.

Dichloromethane extracts of the root bark and stem bark of Kigelia pinnata collected from Zimbabwe exhibited antitrypanosomal activity against Trypanosoma brucei brucei in vitro. Activity-guided fractionation led to the isolation of four naphthoquinones from both the root and stem bark of the plant. The compounds were identified as 2-(1-hydroxyethyl)-naphtho[2,3-b]furan-4,9-quinone (1), isopinnatal (2), kigelinol (3), and isokigelinol (4). Subsequently, the compounds were assessed for antitrypanosomal activity against T. brucei brucei and T. brucei rhodesiense bloodstream form trypomastigotes in vitro. Compound 1 with a furanonaphthoquinone structure was found to possess pronounced activity against both parasites with IC50 values of 0.12 and 0.045 microM, respectively, although it was less active than the standard drug pentamidine. Compounds 2, 3, and 4 also exhibited activity against the parasites, although to a lesser extent. The activities of the compounds were further assessed by comparison with the cytotoxic activities obtained against KB cell lines.