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1.
ACS Infect Dis ; 10(8): 2899-2912, 2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-39087267

RESUMO

The control of malaria, a disease caused by Plasmodium parasites that kills over half a million people every year, is threatened by the continual emergence and spread of drug resistance. Therefore, new molecules with different mechanisms of action are needed in the antimalarial drug development pipeline. Peptides developed from host defense molecules are gaining traction as anti-infectives due to theood of inducing drug resistance. Human platelet factor 4 (PF4) has intrinsic activity against P. falciparum, and a macrocyclic helix-loop-helix peptide derived from its active domain recapitulates this activity. In this study, we used a stepwise approach to optimize first-generation PF4-derived internalization peptides (PDIPs) by producing analogues with substitutions to charged and hydrophobic amino acid residues or with modifications to terminal residues including backbone cyclization. We evaluated the in vitro activity of PDIP analogues against P. falciparum compared to their overall helical structure, resistance to breakdown by serum proteases, selective binding to negatively charged membranes, and hemolytic activity. Next, we combined antiplasmodial potency-enhancing substitutions that retained favorable membrane and cell-selective properties onto the most stable scaffold to produce a backbone cyclic PDIP analogue with four-fold improved activity against P. falciparum compared to first-generation peptides. These studies demonstrate the ability to modify PDIP to select for and combine desirable properties and further validate the suitability of this unique peptide scaffold for developing a new molecule class that is distinct from existing antimalarial drugs.


Assuntos
Antimaláricos , Peptídeos , Plasmodium falciparum , Fator Plaquetário 4 , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/farmacologia , Antimaláricos/química , Humanos , Fator Plaquetário 4/química , Fator Plaquetário 4/farmacologia , Peptídeos/farmacologia , Peptídeos/química , Relação Estrutura-Atividade
2.
Elife ; 132024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38976500

RESUMO

New antimalarial drug candidates that act via novel mechanisms are urgently needed to combat malaria drug resistance. Here, we describe the multi-omic chemical validation of Plasmodium M1 alanyl metalloaminopeptidase as an attractive drug target using the selective inhibitor, MIPS2673. MIPS2673 demonstrated potent inhibition of recombinant Plasmodium falciparum (PfA-M1) and Plasmodium vivax (PvA-M1) M1 metalloaminopeptidases, with selectivity over other Plasmodium and human aminopeptidases, and displayed excellent in vitro antimalarial activity with no significant host cytotoxicity. Orthogonal label-free chemoproteomic methods based on thermal stability and limited proteolysis of whole parasite lysates revealed that MIPS2673 solely targets PfA-M1 in parasites, with limited proteolysis also enabling estimation of the binding site on PfA-M1 to within ~5 Å of that determined by X-ray crystallography. Finally, functional investigation by untargeted metabolomics demonstrated that MIPS2673 inhibits the key role of PfA-M1 in haemoglobin digestion. Combined, our unbiased multi-omic target deconvolution methods confirmed the on-target activity of MIPS2673, and validated selective inhibition of M1 alanyl metalloaminopeptidase as a promising antimalarial strategy.


Assuntos
Antimaláricos , Plasmodium falciparum , Plasmodium vivax , Proteômica , Proteínas de Protozoários , Antimaláricos/farmacologia , Antimaláricos/química , Plasmodium falciparum/enzimologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium vivax/enzimologia , Plasmodium vivax/efeitos dos fármacos , Humanos , Proteínas de Protozoários/metabolismo , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/química , Proteômica/métodos , Aminopeptidases/metabolismo , Aminopeptidases/antagonistas & inibidores , Aminopeptidases/química
3.
mBio ; 15(6): e0096624, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38717141

RESUMO

To combat the global burden of malaria, development of new drugs to replace or complement current therapies is urgently required. Here, we show that the compound MMV1557817 is a selective, nanomolar inhibitor of both Plasmodium falciparum and Plasmodium vivax aminopeptidases M1 and M17, leading to inhibition of end-stage hemoglobin digestion in asexual parasites. MMV1557817 can kill sexual-stage P. falciparum, is active against murine malaria, and does not show any shift in activity against a panel of parasites resistant to other antimalarials. MMV1557817-resistant P. falciparum exhibited a slow growth rate that was quickly outcompeted by wild-type parasites and were sensitized to the current clinical drug, artemisinin. Overall, these results confirm MMV1557817 as a lead compound for further drug development and highlights the potential of dual inhibition of M1 and M17 as an effective multi-species drug-targeting strategy.IMPORTANCEEach year, malaria infects approximately 240 million people and causes over 600,000 deaths, mostly in children under 5 years of age. For the past decade, artemisinin-based combination therapies have been recommended by the World Health Organization as the standard malaria treatment worldwide. Their widespread use has led to the development of artemisinin resistance in the form of delayed parasite clearance, alongside the rise of partner drug resistance. There is an urgent need to develop and deploy new antimalarial agents with novel targets and mechanisms of action. Here, we report a new and potent antimalarial compound, known as MMV1557817, and show that it targets multiple stages of the malaria parasite lifecycle, is active in a preliminary mouse malaria model, and has a novel mechanism of action. Excitingly, resistance to MMV15578117 appears to be self-limiting, suggesting that development of the compound may provide a new class of antimalarial.


Assuntos
Aminopeptidases , Antimaláricos , Plasmodium falciparum , Plasmodium vivax , Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Animais , Camundongos , Plasmodium vivax/efeitos dos fármacos , Plasmodium vivax/enzimologia , Aminopeptidases/antagonistas & inibidores , Aminopeptidases/metabolismo , Resistência a Medicamentos , Humanos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/metabolismo , Proteínas de Protozoários/genética , Feminino
4.
Res Sq ; 2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38746424

RESUMO

New antimalarial drug candidates that act via novel mechanisms are urgently needed to combat malaria drug resistance. Here, we describe the multi-omic chemical validation of Plasmodium M1 alanyl metalloaminopeptidase as an attractive drug target using the selective inhibitor, MIPS2673. MIPS2673 demonstrated potent inhibition of recombinant Plasmodium falciparum ( Pf A-M1) and Plasmodium vivax ( Pv A-M1) M1 metalloaminopeptidases, with selectivity over other Plasmodium and human aminopeptidases, and displayed excellent in vitro antimalarial activity with no significant host cytotoxicity. Orthogonal label-free chemoproteomic methods based on thermal stability and limited proteolysis of whole parasite lysates revealed that MIPS2673 solely targets Pf A-M1 in parasites, with limited proteolysis also enabling estimation of the binding site on Pf A-M1 to within ~5 Å of that determined by X-ray crystallography. Finally, functional investigation by untargeted metabolomics demonstrated that MIPS2673 inhibits the key role of Pf A-M1 in haemoglobin digestion. Combined, our unbiased multi-omic target deconvolution methods confirmed the on-target activity of MIPS2673, and validated selective inhibition of M1 alanyl metalloaminopeptidase as a promising antimalarial strategy.

5.
J Nat Prod ; 87(4): 849-854, 2024 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-38416027

RESUMO

Microthecaline A (1), the known antiplasmodial quinoline serrulatane alkaloid from the roots of Eremophila microtheca F. Muell. ex Benth. (Scrophulariaceae), was targeted for isolation and subsequent use in the generation of a semisynthetic ether library. A large-scale extraction and isolation yielded the previously undescribed quinoline serrulatane microthecaline B (2), along with crystalline 1 that enabled the first X-ray crystallographic analysis to be undertaken on this rare alkaloid structure class. The X-ray diffraction analysis of 1 supported the absolute configuration assignment of microthecaline A, which was originally assigned by ECD data analysis. Microthecaline A (1) was converted into 10 new semisynthetic ether derivatives (3-12) using a diverse series of commercially available alkyl halides. Chemical structures of the new serrulatane alkaloid and semisynthetic ether analogues were assigned by spectroscopic and spectrometric analyses. Antiplasmodial evaluations of 1-12 showed that the semisynthetic derivative 5 elicited the most potent activity with an IC50 value of 7.2 µM against Plasmodium falciparum 3D7 (drug-sensitive) strain.


Assuntos
Alcaloides , Antimaláricos , Plasmodium falciparum , Antimaláricos/farmacologia , Antimaláricos/química , Antimaláricos/isolamento & purificação , Alcaloides/farmacologia , Alcaloides/química , Alcaloides/isolamento & purificação , Plasmodium falciparum/efeitos dos fármacos , Estrutura Molecular , Eremophila (Planta)/química , Cristalografia por Raios X , Quinolinas/farmacologia , Quinolinas/química , Raízes de Plantas/química , Éteres/farmacologia , Éteres/química
6.
Mar Drugs ; 21(5)2023 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-37233511

RESUMO

The incorporation of bromine, iodine or fluorine into the tricyclic core structure of thiaplakortone A (1), a potent antimalarial marine natural product, is reported. Although yields were low, it was possible to synthesise a small nine-membered library using the previously synthesised Boc-protected thiaplakortone A (2) as a scaffold for late-stage functionalisation. The new thiaplakortone A analogues (3-11) were generated using N-bromosuccinimide, N-iodosuccinimide or a Diversinate™ reagent. The chemical structures of all new analogues were fully characterised by 1D/2D NMR, UV, IR and MS data analyses. All compounds were evaluated for their antimalarial activity against Plasmodium falciparum 3D7 (drug-sensitive) and Dd2 (drug-resistant) strains. Incorporation of halogens at positions 2 and 7 of the thiaplakortone A scaffold was shown to reduce antimalarial activity compared to the natural product. Of the new compounds, the mono-brominated analogue (compound 5) displayed the best antimalarial activity with IC50 values of 0.559 and 0.058 µM against P. falciparum 3D7 and Dd2, respectively, with minimal toxicity against a human cell line (HEK293) observed at 80 µM. Of note, the majority of the halogenated compounds showed greater efficacy against the P. falciparum drug-resistant strain.


Assuntos
Antimaláricos , Produtos Biológicos , Malária Falciparum , Humanos , Antimaláricos/farmacologia , Antimaláricos/química , Células HEK293 , Triazinas/química , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum , Produtos Biológicos/química
7.
Microbiol Spectr ; 10(5): e0128221, 2022 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-36094220

RESUMO

The ring-stage survival assay was utilized to assess the impact of physiological hyperoxic stress on dihydroartemisinin (DHA) tolerance for a panel of Plasmodium falciparum strains with and without Kelch13 mutations. Strains without naturally acquired Kelch13 mutations or the postulated genetic background associated with delayed parasite clearance time demonstrated reduced proliferation under hyperoxic conditions in the subsequent proliferation cycle. Dihydroartemisinin tolerance in three isolates with naturally acquired Kelch13 mutations but not two genetically manipulated laboratory strains was modulated by in vitro hyperoxic stress exposure of early-ring-stage parasites in the cycle before drug exposure. Reduced parasite tolerance to additional derivatives, including artemisinin, artesunate, and OZ277, was observed within the second proliferation cycle. OZ439 and epoxomicin completely prevented parasite survival under both hyperoxia and normoxic in vitro culture conditions, highlighting the unique relationship between DHA tolerance and Kelch13 mutation-associated genetic background. IMPORTANCE Artemisinin-based combination therapy (ACT) for treating malaria is under intense scrutiny following treatment failures in the Greater Mekong subregion of Asia. This is further compounded by the potential for extensive loss of life if treatment failures extend to the African continent. Although Plasmodium falciparum has become resistant to all antimalarial drugs, artemisinin "resistance" does not present in the same way as resistance to other antimalarial drugs. Instead, a partial resistance or tolerance is demonstrated, associated with the parasite's genetic profile and linked to a molecular marker referred to as K13. It is suggested that parasites may have adapted to drug treatment, as well as the presence of underlying population health issues such as hemoglobinopathies, and/or environmental pressures, resulting in parasite tolerance to ACT. Understanding parasite evolution and control of artemisinin tolerance will provide innovative approaches to mitigate the development of artemisinin tolerance and thereby artemisinin-based drug treatment failure and loss of life globally to malaria infections.


Assuntos
Antimaláricos , Artemisininas , Hiperóxia , Malária Falciparum , Parasitos , Animais , Plasmodium falciparum/genética , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Artesunato/farmacologia , Artesunato/uso terapêutico , Hiperóxia/tratamento farmacológico , Resistência a Medicamentos/genética , Proteínas de Protozoários/genética , Proteínas de Protozoários/farmacologia , Proteínas de Protozoários/uso terapêutico , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Mutação , Tolerância a Medicamentos , Malária Falciparum/tratamento farmacológico
8.
Bioorg Chem ; 117: 105359, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34689083

RESUMO

Malaria is a devastating disease caused by Plasmodium parasites. Emerging resistance against current antimalarial therapeutics has engendered the need to develop antimalarials with novel structural classes. We recently described the identification and initial optimization of the 2-anilino quinazoline antimalarial class. Here, we refine the physicochemical properties of this antimalarial class with the aim to improve aqueous solubility and metabolism and to reduce adverse promiscuity. We show the physicochemical properties of this class are intricately balanced with asexual parasite activity and human cell cytotoxicity. Structural modifications we have implemented improved LipE, aqueous solubility and in vitro metabolism while preserving fast acting P. falciparum asexual stage activity. The lead compounds demonstrated equipotent activity against P. knowlesi parasites and were not predisposed to resistance mechanisms of clinically used antimalarials. The optimized compounds exhibited modest activity against early-stage gametocytes, but no activity against pre-erythrocytic liver parasites. Confoundingly, the refined physicochemical properties installed in the compounds did not engender improved oral efficacy in a P. berghei mouse model of malaria compared to earlier studies on the 2-anilino quinazoline class. This study provides the framework for further development of this antimalarial class.


Assuntos
Compostos de Anilina/química , Compostos de Anilina/farmacologia , Antimaláricos/química , Antimaláricos/farmacologia , Malária/tratamento farmacológico , Plasmodium/efeitos dos fármacos , Quinazolinas/química , Quinazolinas/farmacologia , Aminação , Compostos de Anilina/uso terapêutico , Animais , Antimaláricos/uso terapêutico , Feminino , Humanos , Malária/parasitologia , Camundongos , Plasmodium/fisiologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/fisiologia , Quinazolinas/uso terapêutico
9.
J Med Chem ; 64(17): 12582-12602, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34437804

RESUMO

A phenotypic high-throughput screen allowed discovery of quinazolinone-2-carboxamide derivatives as a novel antimalarial scaffold. Structure-activity relationship studies led to identification of a potent inhibitor 19f, 95-fold more potent than the original hit compound, active against laboratory-resistant strains of malaria. Profiling of 19f suggested a fast in vitro killing profile. In vivo activity in a murine model of human malaria in a dose-dependent manner constitutes a concomitant benefit.


Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Malária Falciparum/tratamento farmacológico , Quinazolinonas/farmacologia , Administração Oral , Animais , Humanos , Camundongos , Estrutura Molecular , Plasmodium falciparum/efeitos dos fármacos , Quinazolinonas/química , Relação Estrutura-Atividade
10.
ACS Infect Dis ; 7(6): 1680-1689, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-33929818

RESUMO

Prolyl-tRNA synthetase (PRS) is a clinically validated antimalarial target. Screening of a set of PRS ATP-site binders, initially designed for human indications, led to identification of 1-(pyridin-4-yl)pyrrolidin-2-one derivatives representing a novel antimalarial scaffold. Evidence designates cytoplasmic PRS as the drug target. The frontrunner 1 and its active enantiomer 1-S exhibited low-double-digit nanomolar activity against resistant Plasmodium falciparum (Pf) laboratory strains and development of liver schizonts. No cross-resistance with strains resistant to other known antimalarials was noted. In addition, a similar level of growth inhibition was observed against clinical field isolates of Pf and P. vivax. The slow killing profile and the relative high propensity to develop resistance in vitro (minimum inoculum resistance of 8 × 105 parasites at a selection pressure of 3 × IC50) constitute unfavorable features for treatment of malaria. However, potent blood stage and antischizontal activity are compelling for causal prophylaxis which does not require fast onset of action. Achieving sufficient on-target selectivity appears to be particularly challenging and should be the primary focus during the next steps of optimization of this chemical series. Encouraging preliminary off-target profile and oral efficacy in a humanized murine model of Pf malaria allowed us to conclude that 1-(pyridin-4-yl)pyrrolidin-2-one derivatives represent a promising starting point for the identification of novel antimalarial prophylactic agents that selectively target Plasmodium PRS.


Assuntos
Aminoacil-tRNA Sintetases , Antimaláricos , Malária Falciparum , Malária , Animais , Antimaláricos/farmacologia , Humanos , Malária/tratamento farmacológico , Malária Falciparum/tratamento farmacológico , Camundongos , Plasmodium falciparum
11.
J Inorg Biochem ; 219: 111408, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33826972

RESUMO

Reaction of dihydroartemisinin (DHA) with 4-methyl-4'-carboxy-2,2'-bipyridine yielded the new ester derivative L1. Six novel organometallic half-sandwich chlorido Rh(III) and Ir(III) complexes (1-6) containing pentamethylcyclopentadienyl, (Cp*), tetramethylphenylcyclopentadienyl (Cpxph), or tetramethylbiphenylcyclopentadienyl (Cpxbiph), and N,N-chelated bipyridyl group of L1, have been synthesized and characterized. The complexes were screened for inhibitory activity against the Plasmodium falciparum 3D7 (sensitive), Dd2 (multi-drug resistant) and NF54 late stage gametocytes (LSGNF54), the parasite strain Trichomonas vaginalis G3, as well as A2780 (human ovarian carcinoma), A549 (human alveolar adenocarcinoma), HCT116 (human colorectal carcinoma), MCF7 (human breast cancer) and PC3 (human prostate cancer) cancer cell lines. They show nanomolar antiplasmodial activity, outperforming chloroquine and artemisinin. Their activities were also comparable to dihydroartemisinin. As anticancer agents, several of the complexes showed high inhibitory effects, with Ir(III) complex 3, containing the tetramethylbiphenylcyclopentadienyl ligand, having similar IC50 values (concentration for 50% of maximum inhibition of cell growth) as the clinical drug cisplatin (1.06-9.23 µM versus 0.24-7.2 µM, respectively). Overall, the iridium complexes (1-3) are more potent compared to the rhodium derivatives (4-6), and complex 3 emerges as the most promising candidate for future studies.


Assuntos
2,2'-Dipiridil/química , Artemisininas/química , Artemisininas/farmacologia , Irídio/química , Compostos Organometálicos/química , Ródio/química , Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/química , Humanos , Compostos Organometálicos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Trichomonas vaginalis/efeitos dos fármacos
12.
J Med Chem ; 64(7): 4150-4162, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33759519

RESUMO

Novel 3,3'-disubstituted-5,5'-bi(1,2,4-triazine) compounds with potent in vitro activity against Plasmodium falciparum parasites were recently discovered. To improve the pharmacokinetic properties of the triazine derivatives, a new structure-activity relationship (SAR) investigation was initiated with a focus on enhancing the metabolic stability of lead compounds. These efforts led to the identification of second-generation highly potent antimalarial bis-triazines, exemplified by triazine 23, which exhibited significantly improved in vitro metabolic stability (8 and 42 µL/min/mg protein in human and mouse liver microsomes). The disubstituted triazine dimer 23 was also observed to suppress parasitemia in the Peters 4-day test with a mean ED50 value of 1.85 mg/kg/day and exhibited a fast-killing profile, revealing a new class of orally available antimalarial compounds of considerable interest.


Assuntos
Antimaláricos/uso terapêutico , Malária/tratamento farmacológico , Triazinas/uso terapêutico , Animais , Antimaláricos/síntese química , Antimaláricos/farmacocinética , Células CACO-2 , Feminino , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Microssomos Hepáticos/efeitos dos fármacos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/farmacocinética
13.
Eur J Med Chem ; 214: 113253, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33610028

RESUMO

The emerging resistance to combination therapies comprised of artemisinin derivatives has driven a need to identify new antimalarials with novel mechanisms of action. Central to the survival and proliferation of the malaria parasite is the invasion of red blood cells by Plasmodium merozoites, providing an attractive target for novel therapeutics. A screen of the Medicines for Malaria Venture Pathogen Box employing transgenic P. falciparum parasites expressing the nanoluciferase bioluminescent reporter identified the phenylsulfonyl piperazine class as a specific inhibitor of erythrocyte invasion. Here, we describe the optimization and further characterization of the phenylsulfonyl piperazine class. During the optimization process we defined the functionality required for P. falciparum asexual stage activity and determined the alpha-carbonyl S-methyl isomer was important for antimalarial potency. The optimized compounds also possessed comparable activity against multidrug resistant strains of P. falciparum and displayed weak activity against sexual stage gametocytes. We determined that the optimized compounds blocked erythrocyte invasion consistent with the asexual activity observed and therefore the phenylsulfonyl piperazine analogues described could serve as useful tools for studying Plasmodium erythrocyte invasion.


Assuntos
Antimaláricos/farmacologia , Eritrócitos/efeitos dos fármacos , Malária Falciparum/tratamento farmacológico , Piperazinas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium knowlesi/efeitos dos fármacos , Animais , Antimaláricos/síntese química , Antimaláricos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Eritrócitos/parasitologia , Células Hep G2 , Humanos , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Testes de Sensibilidade Parasitária , Piperazinas/síntese química , Piperazinas/química , Solubilidade , Relação Estrutura-Atividade
14.
J Nat Prod ; 83(9): 2641-2646, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32852949

RESUMO

The new 2,3-secoiridoids morisecoiridoic acids A (1) and B (2), the new iridoid 8-acetoxyepishanzilactone (3), and four additional known iridoids (4-7) were isolated from the leaf and stem bark methanol extracts of Morinda asteroscepa using chromatographic methods. The structure of shanzilactone (4) was revised. The purified metabolites were identified using NMR spectroscopic and mass spectrometric techniques, with the absolute configuration of 1 having been established by single-crystal X-ray diffraction analysis. The crude leaf extract (10 µg/mL) and compounds 1-3 and 5 (10 µM) showed mild antiplasmodial activities against the chloroquine-sensitive malaria parasite Plasmodium falciparum (3D7).


Assuntos
Iridoides/química , Morinda/química , Extratos Vegetais/química , Antimaláricos/farmacologia , Iridoides/farmacologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Casca de Planta/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Plasmodium falciparum/efeitos dos fármacos , Difração de Raios X
15.
J Nat Prod ; 83(8): 2390-2398, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32790306

RESUMO

Five new compounds-rhodimer (1), rhodiflavan A (2), rhodiflavan B (3), rhodiflavan C (4), and rhodacarpin (5)-along with 16 known secondary metabolites, were isolated from the CH2Cl2-CH3OH (1:1) extract of the roots of Tephrosia rhodesica. They were identified by NMR spectroscopic, mass spectrometric, X-ray crystallographic, and ECD spectroscopic analyses. The crude extract and the isolated compounds 2-5, 9, 15, and 21 showed activity (100% at 10 µg and IC50 = 5-15 µM) against the chloroquine-sensitive (3D7) strain of Plasmodium falciparum.


Assuntos
Flavonoides/isolamento & purificação , Raízes de Plantas/química , Tephrosia/química , Antimaláricos/farmacologia , Cristalografia por Raios X , Flavonoides/química , Flavonoides/farmacologia , Estrutura Molecular , Plasmodium falciparum/efeitos dos fármacos , Prenilação , Análise Espectral
16.
J Nat Prod ; 83(2): 316-322, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32067457

RESUMO

A new meroisoprenoid (1), two heptenolides (2 and 3), two C-benzylated flavonoids (4 and 5), and 11 known compounds (6-16) were isolated from leaf, stem bark, and root bark extracts of Sphaerocoryne gracilis ssp. gracilis by chromatographic separation. The structures of the new metabolites 1-5 were established by NMR, IR, and UV spectroscopic and mass spectrometric data analysis. (Z)-Sphaerodiol (7), (Z)-acetylmelodorinol (8), 7-hydroxy-6-hydromelodienone (10), and dichamanetin (15) inhibited the proliferation of Plasmodium falciparum (3D7, Dd2) with IC50 values of 1.4-10.5 µM, although these compounds also showed cytotoxicity against human embryonic kidney HEK-293 cells. None of the compounds exhibited significant disruption in protein translation when assayed in vitro.


Assuntos
Antimaláricos/farmacologia , Flavanonas/farmacologia , Flavonoides/isolamento & purificação , Plasmodium falciparum/efeitos dos fármacos , Annonaceae/química , Antimaláricos/química , Flavanonas/química , Flavonoides/química , Células HEK293 , Humanos , Estrutura Molecular , Extratos Vegetais/química , Folhas de Planta/química , Plasmodium berghei/efeitos dos fármacos
17.
J Nat Prod ; 83(2): 422-428, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-31961680

RESUMO

Antiplasmodial high-throughput screening of extracts derived from marine invertebrates collected from northern NSW, Australia, resulted in the methanol extract of the bryozoan Orthoscuticella ventricosa being identified as inhibitory toward the 3D7 strain of Plasmodium falciparum. Purification of this extract resulted in two new bis-ß-carbolines that possess a cyclobutane moiety, orthoscuticellines A and B (1 and 2), three new ß-carboline alkaloids, orthoscuticellines C-E (3-5), and six known compounds, 1-ethyl-4-methylsulfone-ß-carboline (6), 1-ethyl-ß-carboline (7), 1-acetyl-ß-carboline (8) 1-(1'-hydroxyethyl)-ß-carboline (9), 1-methoxycarbonyl-ß-carboline (10), and 1-vinyl-ß-carboline (11). The structures of all compounds were determined from analysis of MS and 1D and 2D NMR data. The compounds showed modest antiplasmodial activity against P. falciparum in the range of 12-21 µM.


Assuntos
Alcaloides/química , Carbolinas/química , Animais , Austrália , Briozoários/química , Carbolinas/isolamento & purificação , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Plasmodium falciparum/efeitos dos fármacos
18.
Molecules ; 24(15)2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31362371

RESUMO

Phytochemical investigations of ethanol root bark and stem bark extracts of Cleistochlamys kirkii (Benth.) Oliv. (Annonaceae) yielded a new benzopyranyl cadinane-type sesquiterpene (cleistonol, 1) alongside 12 known compounds (2-13). The structures of the isolated compounds were established from NMR spectroscopic and mass spectrometric analyses. Structures of compounds 5 and 10 were further confirmed by single crystal X-ray crystallographic analyses, which also established their absolute stereochemical configuration. The ethanolic crude extract of C. kirkii root bark gave 72% inhibition against the chloroquine-sensitive 3D7-strain malaria parasite Plasmodium falciparum at 0.01 µg/mL. The isolated metabolites dichamanetin, (E)-acetylmelodorinol, and cleistenolide showed IC50 = 9.3, 7.6 and 15.2 µM, respectively, against P. falciparum 3D7. Both the crude extract and the isolated compounds exhibited cytotoxicity against the triple-negative, aggressive breast cancer cell line, MDA-MB-231, with IC50 = 42.0 µg/mL (crude extract) and 9.6-30.7 µM (isolated compounds). Our findings demonstrate the potential applicability of C. kirkii as a source of antimalarial and anticancer agents.


Assuntos
Annonaceae/química , Antimaláricos/química , Antimaláricos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Sesquiterpenos Policíclicos/química , Sesquiterpenos Policíclicos/farmacologia , Annonaceae/metabolismo , Humanos , Malária/tratamento farmacológico , Conformação Molecular , Estrutura Molecular , Testes de Sensibilidade Parasitária , Análise Espectral
19.
ChemMedChem ; 14(14): 1329-1335, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31188540

RESUMO

Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N-(3-chloro-4-fluorophenyl)-2-methyl-2-{[4-methyl-3-(morpholinosulfonyl)phenyl]amino}propanamide (compound 28) with low-nanomolar activity against the intraerythrocytic stages of the malaria parasite, and which was found to be inactive in a mammalian cell counter-screen up to 25 µm. Inhibition of gametes in the dual gamete activation assay suggests that this family of compounds may also have transmission blocking capabilities. Whilst we were unable to optimize the aqueous solubility and microsomal stability to a point at which the aminoacetamides would be suitable for in vivo pharmacokinetic and efficacy studies, compound 28 displayed excellent antimalarial potency and selectivity; it could therefore serve as a suitable chemical tool for drug target identification.


Assuntos
Acetamidas/farmacologia , Antimaláricos/farmacologia , Acetamidas/síntese química , Acetamidas/farmacocinética , Animais , Antimaláricos/síntese química , Antimaláricos/farmacocinética , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium berghei/efeitos dos fármacos , Plasmodium cynomolgi/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-Atividade
20.
J Nat Prod ; 82(4): 1019-1023, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-30865443

RESUMO

A new oxidized xanthene, acrotrione (1), and two known acetophenones (2 and 3) were isolated from a methanol extract of the roots of Acronychia pubescens. The structure of 1 was elucidated on the basis of its (+)-HRESIMS, 2D NMR, and ECD data. Acritrione (1) contains an unusual oxidized furo[2,3- c]xanthene moiety that has not been previously reported. Moderate antiplasmodial activity for these natural products against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum was determined with IC50 values ranging from 1.7 to 4.7 µM.


Assuntos
Raízes de Plantas/química , Rutaceae/química , Xantenos/isolamento & purificação , Oxirredução , Xantenos/química
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