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1.
Future Med Chem ; 16(13): 1357-1373, 2024 Jul 02.
Article in English | MEDLINE | ID: mdl-39109436

ABSTRACT

Neglected tropical diseases (NTDs) pose a major threat in tropical zones for impoverished populations. Difficulty of access, adverse effects or low efficacy limit the use of current therapeutic options. Therefore, development of new drugs against NTDs is a necessity. Compounds containing an aminopyridine (AP) moiety are of great interest for the design of new anti-NTD drugs due to their intrinsic properties compared with their closest chemical structures. Currently, over 40 compounds with an AP moiety are on the market, but none is used against NTDs despite active research on APs. The aim of this review is to present the medicinal chemistry work carried out with these scaffolds, against protozoan NTDs: Trypanosoma cruzi, Trypanosoma brucei or Leishmania spp.


[Box: see text].


Subject(s)
Aminopyridines , Antiprotozoal Agents , Neglected Diseases , Trypanosoma brucei brucei , Trypanosoma cruzi , Neglected Diseases/drug therapy , Humans , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/chemical synthesis , Trypanosoma cruzi/drug effects , Aminopyridines/chemistry , Aminopyridines/pharmacology , Trypanosoma brucei brucei/drug effects , Leishmania/drug effects , Drug Development , Parasitic Sensitivity Tests , Animals
2.
J Enzyme Inhib Med Chem ; 39(1): 2377586, 2024 Dec.
Article in English | MEDLINE | ID: mdl-39037009

ABSTRACT

Species of Leishmania and Trypanosoma genera are the causative agents of relevant parasitic diseases. Survival inside their hosts requires the existence of a potent antioxidant enzymatic machinery. Four iron superoxide dismutases have been described in trypanosomatids (FeSODA, FeSODB1, FeSODB2, and FeSODC) that hold a potential as therapeutic targets. Nonetheless, very few studies have been developed that make use of the purified enzymes. Moreover, FeSODC remains uncharacterised in Leishmania. In this work, for the first time, we describe the purification and enzymatic activity of recombinant versions of the four Leishmania FeSOD isoforms and establish an improved strategy for developing inhibitors. We propose a novel parameter [(V*cyt. c - Vcyt. c)/Vcyt. c] which, in contrast to that used in the classical cytochrome c reduction assay, correlates linearly with enzyme concentration. As a proof of concept, we determine the IC50 values of two ruthenium carbosilane metallodendrimers against these isoforms.


Subject(s)
Antiprotozoal Agents , Dose-Response Relationship, Drug , Leishmania infantum , Parasitic Sensitivity Tests , Superoxide Dismutase , Leishmania infantum/enzymology , Leishmania infantum/drug effects , Structure-Activity Relationship , Molecular Structure , Superoxide Dismutase/metabolism , Superoxide Dismutase/antagonists & inhibitors , Superoxide Dismutase/chemistry , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/chemical synthesis , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesis , Leishmaniasis/drug therapy , Leishmaniasis/parasitology
3.
Mar Drugs ; 22(7)2024 Jun 30.
Article in English | MEDLINE | ID: mdl-39057418

ABSTRACT

The current 2019-2021 marine pharmacology literature review provides a continuation of previous reviews covering the period 1998 to 2018. Preclinical marine pharmacology research during 2019-2021 was published by researchers in 42 countries and contributed novel mechanism-of-action pharmacology for 171 structurally characterized marine compounds. The peer-reviewed marine natural product pharmacology literature reported antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral mechanism-of-action studies for 49 compounds, 87 compounds with antidiabetic and anti-inflammatory activities that also affected the immune and nervous system, while another group of 51 compounds demonstrated novel miscellaneous mechanisms of action, which upon further investigation, may contribute to several pharmacological classes. Thus, in 2019-2021, a very active preclinical marine natural product pharmacology pipeline provided novel mechanisms of action as well as new lead chemistry for the clinical marine pharmaceutical pipeline targeting the therapy of several disease categories.


Subject(s)
Anti-Inflammatory Agents , Antitubercular Agents , Antiviral Agents , Aquatic Organisms , Biological Products , Hypoglycemic Agents , Humans , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/chemistry , Biological Products/pharmacology , Biological Products/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antitubercular Agents/pharmacology , Antitubercular Agents/chemistry , Nervous System/drug effects , Immune System/drug effects , Antifungal Agents/pharmacology , Antifungal Agents/chemistry , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry
4.
Bioorg Med Chem Lett ; 110: 129876, 2024 Sep 15.
Article in English | MEDLINE | ID: mdl-38964519

ABSTRACT

In this study, we present the design, synthesis, and cytotoxic evaluation of a series of benzimidazole N-acylhydrazones against strains of T. cruzi (Y and Tulahuen) and Leishmania species (L. amazonensis and L. infantum). Compound (E)-N'-((5-Nitrofuran-2-yl)methylene)-1H-benzo[d]imidazole-2-carbohydrazide demonstrated significant activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC50/120 h of 0.033 µM and a selectivity index (SI) of 7680. This represents a potency 46 times greater than that of benznidazole (IC50/120 h = 1.520 µM, SI = 1390). Another compound (E)-N'-(2-Hydroxybenzylidene)-1H-benzo[d]imidazole-2-carbohydrazide showed promising activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC50/120 h of 3.600 µM and an SI of 14.70. However, its efficacy against L. infantum and L. amazonensis was comparatively lower. These findings provide valuable insights for the development of more effective treatments against Trypanosoma cruzi.


Subject(s)
Benzimidazoles , Hydrazones , Leishmania infantum , Trypanosoma cruzi , Trypanosoma cruzi/drug effects , Hydrazones/pharmacology , Hydrazones/chemistry , Hydrazones/chemical synthesis , Structure-Activity Relationship , Leishmania infantum/drug effects , Benzimidazoles/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/chemical synthesis , Molecular Structure , Parasitic Sensitivity Tests , Dose-Response Relationship, Drug , Leishmania/drug effects , Trypanocidal Agents/pharmacology , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/chemistry , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/chemistry , Animals
5.
Chem Biol Drug Des ; 104(1): e14585, 2024 Jul.
Article in English | MEDLINE | ID: mdl-39013834

ABSTRACT

Leishmaniasis is a disease caused by protozoa Leishmania spp., considered as a significant and urgent public health problem mainly in developing countries. In the absence of an effective vaccine, the treatment of infected people is one of the most commonly prophylactic measures used to control this disease. However, the therapeutic arsenal is reduced to a few drugs, with serious side effects and variability in efficacy. Attempting to this problem, in this work, a series of benzothiazole derivatives was synthetized and assayed against promastigotes and intracellular amastigotes of L. amazonensis, as well as the toxicity on macrophages. In addition, studies about the mechanism of action were also performed. Among the synthesized molecules, the substitution at position 4 of the aromatic ring appears to be critical for activity. The best compound exhibited IC50 values of 28.86 and 7.70 µM, against promastigotes and amastigotes of L. amazonensis, respectively, being more active than miltefosine, used as reference drug. The in silico analysis of physicochemical and pharmacokinetic (ADMET) properties of this compound suggested a good profile of oral bioavailability and safety. In conclusion, the strategy of using benzothiazole nucleous in the search for new antileishmanial agents was advantageous and preliminar data provide information about the mechanism of action as well as in silico parameters suggest a good profile for preclinical studies.


Subject(s)
Antiprotozoal Agents , Benzothiazoles , Hydrazones , Leishmania , Benzothiazoles/chemistry , Benzothiazoles/pharmacology , Benzothiazoles/chemical synthesis , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/chemical synthesis , Animals , Hydrazones/chemistry , Hydrazones/pharmacology , Hydrazones/chemical synthesis , Mice , Leishmania/drug effects , Macrophages/drug effects , Macrophages/parasitology , Structure-Activity Relationship , Humans
6.
Chem Biol Interact ; 399: 111156, 2024 Aug 25.
Article in English | MEDLINE | ID: mdl-39029856

ABSTRACT

Leishmaniases, caused by Leishmania parasites, are widespread and pose significant health risks globally. Visceral leishmaniasis (VL) is particularly prevalent in Brazil, with high morbidity and mortality rates. Traditional treatments, such as pentavalent antimonials, have limitations due to toxicity and resistance. Therefore, exploring new compounds like lectins is crucial. Concanavalin A (ConA) has shown promise in inhibiting Leishmania growth. This study aimed to evaluate its leishmanicidal effect on L. infantum promastigotes and understand its mechanism of action. In vitro tests demonstrated inhibition of promastigote growth when treated with ConA, with IC50 values ranging from 3 to 5 µM over 24-72 h. This study suggests that ConA interacts with L. infantum glycans. Additionally, ConA caused damage to the membrane integrity of parasites and induced ROS production, contributing to parasite death. Scanning electron microscopy confirmed morphological alterations in treated promastigotes. ConA combined with the amphotericin B (AmB) showed synergistic effects, reducing the required dose of AmB, and potentially mitigating its toxicity. ConA demonstrated no cytotoxic effects on macrophages, instead stimulating their proliferation. These findings reinforce that lectin exhibits promising leishmanicidal activity against L. infantum promastigotes, making ConA a potential candidate for leishmaniasis treatment.


Subject(s)
Antiprotozoal Agents , Canavalia , Concanavalin A , Leishmania infantum , Leishmania infantum/drug effects , Concanavalin A/pharmacology , Animals , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , Seeds/chemistry , Reactive Oxygen Species/metabolism , Mice , Amphotericin B/pharmacology , Lectins/pharmacology , Lectins/chemistry , Lectins/metabolism , Plant Lectins/pharmacology , Plant Lectins/chemistry , Macrophages/drug effects , Macrophages/metabolism , Macrophages/parasitology
7.
ACS Infect Dis ; 10(8): 2467-2484, 2024 Aug 09.
Article in English | MEDLINE | ID: mdl-38950147

ABSTRACT

Millions of people worldwide are affected by leishmaniasis, caused by the Leishmania parasite. Effective treatment is challenging due to the biological complexity of the parasite, drug toxicity, and increasing resistance to conventional drugs. To combat this disease, the development of specific strategies to target and selectively eliminate the parasite is crucial. This Review highlights the importance of amino acids in the developmental stages of Leishmania as a factor determining whether the infection progresses or is suppressed. It also explores the use of peptides as alternatives in parasite control and the development of novel targeted treatments. While these strategies show promise for more effective and targeted treatment, further studies to address the remaining challenges are imperative.


Subject(s)
Amino Acids , Antiprotozoal Agents , Leishmania , Leishmaniasis , Peptides , Leishmania/drug effects , Amino Acids/chemistry , Leishmaniasis/drug therapy , Leishmaniasis/parasitology , Humans , Peptides/pharmacology , Peptides/chemistry , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , Animals
8.
ACS Infect Dis ; 10(8): 2755-2774, 2024 Aug 09.
Article in English | MEDLINE | ID: mdl-38953453

ABSTRACT

Folate enzymes, namely, dihydrofolate reductase (DHFR) and pteridine reductase (PTR1) are acknowledged targets for the development of antiparasitic agents against Trypanosomiasis and Leishmaniasis. Based on the amino dihydrotriazine motif of the drug Cycloguanil (Cyc), a known inhibitor of both folate enzymes, we have identified two novel series of inhibitors, the 2-amino triazino benzimidazoles (1) and 2-guanidino benzimidazoles (2), as their open ring analogues. Enzymatic screening was carried out against PTR1, DHFR, and thymidylate synthase (TS). The crystal structures of TbDHFR and TbPTR1 in complex with selected compounds experienced in both cases a substrate-like binding mode and allowed the rationalization of the main chemical features supporting the inhibitor ability to target folate enzymes. Biological evaluation of both series was performed against T. brucei and L. infantum and the toxicity against THP-1 human macrophages. Notably, the 5,6-dimethyl-2-guanidinobenzimidazole 2g resulted to be the most potent (Ki = 9 nM) and highly selective TbDHFR inhibitor, 6000-fold over TbPTR1 and 394-fold over hDHFR. The 5,6-dimethyl tricyclic analogue 1g, despite showing a lower potency and selectivity profile than 2g, shared a comparable antiparasitic activity against T. brucei in the low micromolar domain. The dichloro-substituted 2-guanidino benzimidazoles 2c and 2d revealed their potent and broad-spectrum antitrypanosomatid activity affecting the growth of T. brucei and L. infantum parasites. Therefore, both chemotypes could represent promising templates that could be valorized for further drug development.


Subject(s)
Folic Acid Antagonists , Tetrahydrofolate Dehydrogenase , Triazines , Trypanosoma brucei brucei , Trypanosoma brucei brucei/drug effects , Trypanosoma brucei brucei/enzymology , Humans , Tetrahydrofolate Dehydrogenase/metabolism , Tetrahydrofolate Dehydrogenase/chemistry , Folic Acid Antagonists/pharmacology , Folic Acid Antagonists/chemistry , Triazines/pharmacology , Triazines/chemistry , Trypanocidal Agents/pharmacology , Trypanocidal Agents/chemistry , Proguanil/pharmacology , Proguanil/chemistry , Thymidylate Synthase/antagonists & inhibitors , Thymidylate Synthase/chemistry , Thymidylate Synthase/metabolism , Leishmania infantum/drug effects , Leishmania infantum/enzymology , Benzimidazoles/pharmacology , Benzimidazoles/chemistry , Structure-Activity Relationship , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , Protozoan Proteins/antagonists & inhibitors , Protozoan Proteins/metabolism , Protozoan Proteins/chemistry , Oxidoreductases
9.
Bioorg Med Chem Lett ; 110: 129883, 2024 Sep 15.
Article in English | MEDLINE | ID: mdl-39013490

ABSTRACT

The protozoan parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. are responsible for continued propagation of neglected tropical diseases such as African sleeping sickness, Chagas disease and leishmaniasis respectively. Following a report that captopril targets Leishmania donovani dipeptidyl carboxypeptidase, a series of simple proline amides and captopril analogues were synthesized and found to exhibit 1-2 µM in vitro inhibition and selectivity against Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. The results were corroborated with computational docking studies. Arguably, the synthetic proline amides represent the structurally simplest examples of in vitro pan antiprotozoal compounds.


Subject(s)
Captopril , Trypanosoma brucei brucei , Trypanosoma cruzi , Captopril/pharmacology , Captopril/chemistry , Captopril/chemical synthesis , Trypanosoma brucei brucei/drug effects , Trypanosoma brucei brucei/enzymology , Trypanosoma cruzi/drug effects , Trypanosoma cruzi/enzymology , Structure-Activity Relationship , Molecular Docking Simulation , Trypanocidal Agents/pharmacology , Trypanocidal Agents/chemistry , Trypanocidal Agents/chemical synthesis , Molecular Structure , Leishmania/drug effects , Leishmania/enzymology , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/chemical synthesis , Humans
10.
ACS Infect Dis ; 10(8): 2913-2928, 2024 Aug 09.
Article in English | MEDLINE | ID: mdl-39023360

ABSTRACT

The lack of effective vaccines and the development of resistance to the current treatments highlight the urgent need for new anti-leishmanials. Sphingolipid metabolism has been proposed as a promising source of Leishmania-specific targets as these lipids are key structural components of the eukaryotic plasma membrane and are involved in distinct cellular events. Inositol phosphorylceramide (IPC) is the primary sphingolipid in the Leishmania species and is the product of a reaction mediated by IPC synthase (IPCS). The antihistamine clemastine fumarate has been identified as an inhibitor of IPCS in L. major and a potent anti-leishmanial in vivo. Here we sought to further examine the target of this compound in the more tractable species L. mexicana, using an approach combining genomic, proteomic, metabolomic and lipidomic technologies, with molecular and biochemical studies. While the data demonstrated that the response to clemastine fumarate was largely conserved, unexpected disturbances beyond sphingolipid metabolism were identified. Furthermore, while deletion of the gene encoding LmxIPCS had little impact in vitro, it did influence clemastine fumarate efficacy and, importantly, in vivo pathogenicity. Together, these data demonstrate that clemastine does inhibit LmxIPCS and cause associated metabolic disturbances, but its primary target may lie elsewhere.


Subject(s)
Antiprotozoal Agents , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , Sphingolipids/metabolism , Hexosyltransferases/genetics , Hexosyltransferases/metabolism , Hexosyltransferases/antagonists & inhibitors , Leishmania/drug effects , Leishmania/genetics , Leishmania/enzymology , Animals , Leishmania mexicana/drug effects , Leishmania mexicana/genetics , Leishmania mexicana/enzymology , Glycosphingolipids/metabolism , Transferases (Other Substituted Phosphate Groups)/genetics , Transferases (Other Substituted Phosphate Groups)/metabolism
11.
Molecules ; 29(11)2024 May 24.
Article in English | MEDLINE | ID: mdl-38893370

ABSTRACT

Kallopterolides A-I (1-9), a family of nine diterpenoids possessing either a cleaved pseudopterane or a severed cembrane skeleton, along with several known compounds were isolated from the Caribbean Sea plume Antillogorgia kallos. The structures and relative configurations of 1-9 were characterized by analysis of HR-MS, IR, UV, and NMR spectroscopic data in addition to computational methods and side-by-side comparisons with published NMR data of related congeners. An investigation was conducted as to the potential of the kallopterolides as plausible in vitro anti-inflammatory, antiprotozoal, and antituberculosis agents.


Subject(s)
Anthozoa , Diterpenes , Diterpenes/chemistry , Diterpenes/isolation & purification , Diterpenes/pharmacology , Animals , Anthozoa/chemistry , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/isolation & purification , Caribbean Region , Molecular Structure , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/isolation & purification , Magnetic Resonance Spectroscopy , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Antitubercular Agents/isolation & purification
12.
PLoS One ; 19(6): e0301901, 2024.
Article in English | MEDLINE | ID: mdl-38870204

ABSTRACT

Herein we report the design and the synthesis of a library of new and more hydrophilic bisindole analogues based on our previously identified antileishmanial compound URB1483 that failed the preliminary in vivo test. The novel bisindoles were phenotypically screened for efficacy against Leishmania infantum promastigotes and simultaneously for toxicity on human macrophage-like THP-1 cells. Among the less toxic compounds, eight bisindoles showed IC50 below 10 µM. The most selective compound 1h (selectivity index = 10.1, comparable to miltefosine) and the most potent compound 2c (IC50 = 2.7 µM) were tested for their efficacy on L. infantum intracellular amastigotes. The compounds also demonstrated their efficacy in the in vitro infection model, showing IC50 of 11.1 and 6.8 µM for 1h and 2c, respectively. Moreover, 1h showed a better toxicity profile than the commercial drug miltefosine. For all these reasons, 1h could be a possible new starting point for hydrophilic antileishmanial agents with low cytotoxicity on human macrophage-like cells.


Subject(s)
Antiprotozoal Agents , Leishmania infantum , Leishmania infantum/drug effects , Humans , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , THP-1 Cells , Indoles/pharmacology , Indoles/chemistry , Hydrophobic and Hydrophilic Interactions , Phosphorylcholine/analogs & derivatives , Phosphorylcholine/pharmacology , Phosphorylcholine/chemistry , Macrophages/drug effects , Macrophages/parasitology , Inhibitory Concentration 50
13.
Sci Rep ; 14(1): 13610, 2024 06 13.
Article in English | MEDLINE | ID: mdl-38871751

ABSTRACT

Natural products play a significant role in providing the current demand as antiparasitic agents, which offer an attractive approach for the discovery of novel drugs. The present study aimed to evaluate in vitro the potential impact of seaweed Padina pavonica (P. pavonica) extract in combating Acanthamoeba castellanii (A. castellanii). The phytochemical constituents of the extract were characterized by Gas chromatography-mass spectrometry. Six concentrations of the algal extract were used to evaluate its antiprotozoal activity at various incubation periods. Our results showed that the extract has significant inhibition against trophozoites and cysts viability, with complete inhibition at the high concentrations. The IC50 of P. pavonica extract was 4.56 and 4.89 µg/mL for trophozoites and cysts, respectively, at 24 h. Morphological alterations of A. castellanii trophozoites/cysts treated with the extract were assessed using inverted and scanning electron microscopes and showed severe damage features upon treatment with the extract at different concentrations. Molecular Docking of extracted compounds against Acanthamoeba cytochrome P450 monooxygenase (AcCYP51) was performed using Autodock vina1.5.6. A pharmacokinetic study using SwissADME was also conducted to investigate the potentiality of the identified bioactive compounds from Padina extract to be orally active drug candidates. In conclusion, this study highlights the in vitro amoebicidal activity of P. pavonica extract against A. castellanii adults and cysts and suggests potential AcCYP51 inhibition.


Subject(s)
Acanthamoeba Keratitis , Acanthamoeba castellanii , Molecular Docking Simulation , Plant Extracts , Acanthamoeba castellanii/drug effects , Acanthamoeba Keratitis/drug therapy , Acanthamoeba Keratitis/parasitology , Plant Extracts/pharmacology , Plant Extracts/chemistry , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , Trophozoites/drug effects , Animals , Humans
14.
Int J Mol Sci ; 25(11)2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38892424

ABSTRACT

Parasitic diseases, predominantly prevalent in developing countries, are increasingly spreading to high-income nations due to shifting migration patterns. The World Health Organization (WHO) estimates approximately 300 million annual cases of giardiasis. The emergence of drug resistance and associated side effects necessitates urgent research to address this growing health concern. In this study, we evaluated over eleven thousand pharmacological compounds sourced from the FDA database to assess their impact on the TATA-binding protein (TBP) of the early diverging protist Giardia lamblia, which holds medical significance. We identified a selection of potential pharmacological compounds for combating this parasitic disease through in silico analysis, employing molecular modeling techniques such as homology modeling, molecular docking, and molecular dynamics simulations. Notably, our findings highlight compounds DB07352 and DB08399 as promising candidates for inhibiting the TBP of Giardia lamblia. Also, these compounds and DB15584 demonstrated high efficacy against trophozoites in vitro. In summary, this study identifies compounds with the potential to combat giardiasis, offering the prospect of specific therapies and providing a robust foundation for future research.


Subject(s)
Antiprotozoal Agents , Giardia lamblia , Giardiasis , Molecular Docking Simulation , United States Food and Drug Administration , Giardiasis/drug therapy , Giardia lamblia/drug effects , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , United States , Humans , Protozoan Proteins/chemistry , Protozoan Proteins/metabolism , Protozoan Proteins/antagonists & inhibitors , Molecular Dynamics Simulation
15.
Dalton Trans ; 53(27): 11295-11309, 2024 Jul 09.
Article in English | MEDLINE | ID: mdl-38898716

ABSTRACT

A thiophene-derived Schiff base ligand (E)-2-morpholino-N-(thiophen-2-ylmethylene)ethanamine was used for the synthesis of M(II) complexes, [TEM(M)X2] (M = Co, Cu, Zn; X = Cl; M = Cd, X = Br). Structural characterization of the synthesized complexes revealed distorted tetrahedral geometry around the M(II) center. In vitro investigation of the synthesized ligand and its M(II) complexes showed considerable anti-urease and leishmanicidal potential. The synthesized complexes also exhibited a significant inhibitory effect on urease, with IC50 values in the range of 3.50-8.05 µM. In addition, the docking results were consistent with the experimental results. A preliminary study of human colorectal cancer (HCT), hepatic cancer (HepG2), and breast cancer (MCF-7) cell lines showed marked anticancer activities of these complexes.


Subject(s)
Antineoplastic Agents , Coordination Complexes , Molecular Docking Simulation , Schiff Bases , Thiophenes , Urease , Humans , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Urease/antagonists & inhibitors , Urease/metabolism , Thiophenes/chemistry , Thiophenes/pharmacology , Thiophenes/chemical synthesis , Schiff Bases/chemistry , Schiff Bases/pharmacology , Schiff Bases/chemical synthesis , Morpholines/chemistry , Morpholines/pharmacology , Morpholines/chemical synthesis , Cell Line, Tumor , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesis , Molecular Structure , Leishmania/drug effects , Structure-Activity Relationship , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/chemical synthesis , Drug Screening Assays, Antitumor
16.
Acta Trop ; 257: 107291, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38889863

ABSTRACT

Owing to the persistent number of parasitic deaths, Visceral leishmaniasis continues to haunt several economically weaker sections of India. The disease causes over 30,000 deaths and threatens millions annually on a global scale. The standard pentavalent antimonials, on the other hand, are associated with health adversities and disease relapse. The current study is focused on the search for the most potential natural bioactive phytocompound from the bark extract of the Northeastern Indian plant, Garcinia cowa, that shows potent anti-leishmanial properties. The High Resonance Liquid Chromatography followed by Mass Spectrometry (HR-LCMS) study followed by an in silico molecular docking using computational tools revealed that α-mangostin might potentially possess antiparasitic activity. To validate the anti-leishmanial efficacy of the compound, a cell viability assay was performed, which demonstrated the parasite-specific inhibitory activity of α-mangostin; with IC50 values ranging from 4.95 - 7.37 µM against the different forms of Leishmania donovani parasite. The flow cytometric analysis of the phytocompound treated parasites indicated an oxidative and nitrosative stress-mediated apoptotic cell death in the parasites, by the suggestive surge in nuclear fragmentation and mitochondrial dysfunction. Simultaneously, a cytokine profiling study suggested approximate two-to-three-fold upregulated levels of pro-inflammatory cytokines post-compound treatment, which is predicted to actively contribute to parasite-killing. α-mangostin was also found to reduce the chances of parasite survival by inhibiting arginase enzyme activity, which in favorable conditions facilitates its sustenance. This study thereby substantiates that α-mangostin significantly possesses anti-leishmanial potentiality that can be developed into a cure for this infectious disease.


Subject(s)
Antiprotozoal Agents , Garcinia , Leishmania donovani , Molecular Docking Simulation , Plant Extracts , Xanthones , Xanthones/pharmacology , Xanthones/chemistry , Garcinia/chemistry , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , Plant Extracts/pharmacology , Plant Extracts/chemistry , Leishmania donovani/drug effects , Cell Survival/drug effects , India , Cytokines/metabolism , Plant Bark/chemistry , Inhibitory Concentration 50 , Animals , Humans , Apoptosis/drug effects
17.
Parasitol Res ; 123(6): 241, 2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38864931

ABSTRACT

Managing primary amoebic meningoencephalitis, induced by Naegleria fowleri poses a complex medical challenge. There is currently no specific anti-amoebic drug that has proven effectiveness against N. fowleri infection. Ongoing research endeavours are dedicated to uncovering innovative treatment strategies, including the utilization of drugs and immune modulators targeting Naegleria infection. In this study, we explored the potential of imidazo[2,1-b]thiazole and imidazooxazole derivatives that incorporate sulfonate and sulfamate groups as agents with anti-amoebic properties against N. fowleri. We assessed several synthesized compounds (1f, 1m, 1q, 1s, and 1t) for their efficacy in eliminating amoebae, their impact on cytotoxicity, and their influence on the damage caused to human cerebral microvascular endothelial (HBEC-5i) cells when exposed to the N. fowleri (ATCC 30174) strain. The outcomes revealed that, among the five compounds under examination, 1m, 1q, and 1t demonstrated notable anti-parasitic effects against N. fowleri (P ≤ 0.05). Compound 1t exhibited the highest anti-parasitic activity, reducing N. fowleri population by 80%. Additionally, three compounds, 1m, 1q, and 1t, significantly mitigated the damage inflicted on host cells by N. fowleri. However, the results of cytotoxicity analysis indicated that while 1m and 1q had minimal cytotoxic effects on endothelial cells, compound 1t caused moderate cytotoxicity (34%). Consequently, we conclude that imidazo[2,1-b]thiazole and imidazooxazole derivatives containing sulfonate and sulfamate groups exhibit a marked capacity to eliminate amoebae viability while causing limited toxicity to human cells. In aggregate, these findings hold promise that could potentially evolve into novel therapeutic options for treating N. fowleri infection.


Subject(s)
Antiprotozoal Agents , Endothelial Cells , Naegleria fowleri , Thiazoles , Humans , Thiazoles/pharmacology , Thiazoles/chemistry , Naegleria fowleri/drug effects , Endothelial Cells/drug effects , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/chemical synthesis , Cell Line , Imidazoles/pharmacology , Imidazoles/chemistry , Imidazoles/chemical synthesis , Oxazoles/pharmacology , Oxazoles/chemistry , Cell Survival/drug effects
18.
ACS Infect Dis ; 10(6): 2002-2017, 2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38753953

ABSTRACT

Leishmaniasis is a neglected tropical disease; there is currently no vaccine and treatment is reliant upon a handful of drugs suffering from multiple issues including toxicity and resistance. There is a critical need for development of new fit-for-purpose therapeutics, with reduced toxicity and targeting new mechanisms to overcome resistance. One enzyme meriting investigation as a potential drug target in Leishmania is M17 leucyl-aminopeptidase (LAP). Here, we aimed to chemically validate LAP as a drug target in L. major through identification of potent and selective inhibitors. Using RapidFire mass spectrometry, the compounds DDD00057570 and DDD00097924 were identified as selective inhibitors of recombinant Leishmania major LAP activity. Both compounds inhibited in vitro growth of L. major and L. donovani intracellular amastigotes, and overexpression of LmLAP in L. major led to reduced susceptibility to DDD00057570 and DDD00097924, suggesting that these compounds specifically target LmLAP. Thermal proteome profiling revealed that these inhibitors thermally stabilized two M17 LAPs, indicating that these compounds selectively bind to enzymes of this class. Additionally, the selectivity of the inhibitors to act on LmLAP and not against the human ortholog was demonstrated, despite the high sequence similarities LAPs of this family share. Collectively, these data confirm LmLAP as a promising therapeutic target for Leishmania spp. that can be selectively inhibited by drug-like small molecules.


Subject(s)
Antiprotozoal Agents , Leishmania major , Leishmania major/enzymology , Leishmania major/drug effects , Leishmania major/genetics , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , Protozoan Proteins/metabolism , Protozoan Proteins/antagonists & inhibitors , Protozoan Proteins/genetics , Protozoan Proteins/chemistry , Animals , Humans , Leishmania donovani/enzymology , Leishmania donovani/drug effects , Leishmania donovani/genetics
19.
Mol Biochem Parasitol ; 259: 111629, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38750697

ABSTRACT

Leishmaniases comprise a group of infectious parasitic diseases caused by various species of Leishmania and are considered a significant public health problem worldwide. Only a few medications, including miltefosine, amphotericin B, and meglumine antimonate, are used in current therapy. These medications are associated with severe side effects, low efficacy, high cost, and the need for hospital support. Additionally, there have been occurrences of drug resistance. Additionally, only a limited number of drugs, such as meglumine antimonate, amphotericin B, and miltefosine, are available, all of which are associated with severe side effects. In this context, the need for new effective drugs with fewer adverse effects is evident. Therefore, this study investigated the anti-Leishmania activity of a dichloromethane fraction (DCMF) extracted from Arrabidaea brachypoda roots. This fraction inhibited the viability of L. infantum, L. braziliensis, and L. Mexicana promastigotes, with IC50 values of 10.13, 11.44, and 11.16 µg/mL, respectively, and against L. infantum amastigotes (IC50 = 4.81 µg/mL). Moreover, the DCMF exhibited moderate cytotoxicity (CC50 = 25.15) towards RAW264.7 macrophages, with a selectivity index (SI) of 5.2. Notably, the DCMF caused damage to the macrophage genome only at 40 µg/mL, which is greater than the IC50 found for all Leishmania species. The results suggest that DCMF demonstrates similar antileishmanial effectiveness to isolated brachydin B, without causing genotoxic effects on mammalian cells. This finding is crucial because the isolation of the compounds relies on several steps and is very costly while obtaining the DCMF fraction is a simple and cost-effective process. Furthermore, In addition, the potential mechanisms of action of brachydins were also investigated. The computational analysis indicates that brachydin compounds bind to the Triosephosphate isomerase (TIM) enzyme via two main mechanisms: destabilizing the interface between the homodimers and interacting with catalytic residues situated at the site of binding. Based on all the results, DCMF exhibits promise as a therapeutic agent for leishmaniasis due to its significantly reduced toxicity in comparison to the adverse effects associated with current reference treatments.


Subject(s)
Antiprotozoal Agents , Bignoniaceae , Flavonoids , Leishmania , Molecular Docking Simulation , Plant Extracts , Bignoniaceae/chemistry , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/isolation & purification , Flavonoids/pharmacology , Flavonoids/chemistry , Animals , Leishmania/drug effects , Leishmania/genetics , Plant Extracts/pharmacology , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Mice , Inhibitory Concentration 50 , Macrophages/drug effects , Macrophages/parasitology , RAW 264.7 Cells
20.
Int J Pharm ; 660: 124275, 2024 Jul 20.
Article in English | MEDLINE | ID: mdl-38797252

ABSTRACT

Poor drug penetration, emerging drug resistance, and systemic toxicity are among the major obstacles challenging the current treatment of cutaneous leishmaniasis. Hence, developing advanced strategies for effective and targeted delivery of antileishmanial agents is crucial. Several drug delivery carriers have been developed till current date for dermal/transdermal delivery, especially those which are fabricated using eco-friendly synthesis approaches, since they protect the environment from the harmful effects of chemical waste disposal. This work describes the preparation of selenium nanoparticles loaded with silymarin via one-pot green reduction technique, for treatment of cutaneous leishmaniasis. The selected silymarin loaded selenium nanoparticles (SSNs4-0.1) displayed good loading efficiency of 58.22 ± 0.56 %, zeta potential of -30.63 ± 0.40 mV, hydrodynamic diameter of 245.77 ± 11.12 nm, and polydispersity index of 0.19 ± 0.01. It exhibited good physical stability, as well as high ex vivo deposition % in the epidermis (46.98 ± 1.51 %) and dermis (35.23 ± 1.72 %), which was further proven using confocal laser microscopy. It also exhibited significant cytocompatibility and noticeable cellular internalization of 90.02 ± 3.81 % in human fibroblasts, as well as high trypanothione reductase inhibitory effect (97.10 ± 0.30 %). Results of this study confirmed the successful green synthesis of silymarin-loaded selenium nanoparticles; delineating them as one of the promising antileishmanial topical delivery systems.


Subject(s)
Antiprotozoal Agents , Drug Carriers , Green Chemistry Technology , Nanoparticles , Selenium , Silymarin , Selenium/chemistry , Selenium/administration & dosage , Antiprotozoal Agents/administration & dosage , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacokinetics , Humans , Silymarin/administration & dosage , Silymarin/chemistry , Silymarin/pharmacology , Silymarin/pharmacokinetics , Drug Carriers/chemistry , Nanoparticles/chemistry , Green Chemistry Technology/methods , Animals , Administration, Cutaneous , Leishmaniasis, Cutaneous/drug therapy , Fibroblasts/drug effects , Cell Survival/drug effects , Cell Line
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