Antiplasmodial activity of sulfonylhydrazones: in vitro and in silico approaches

2020 ◽  
Author(s):  
Fernando de Moura Gatti ◽  
Renan Augusto Gomes ◽  
Amanda Luisa da Fonseca ◽  
Elys Juliane Cardoso Lima ◽  
Drielli Gomes Vital-Fujii ◽  
...  
Keyword(s):  
Antiplasmodial Activity ◽  
Public Health Issue ◽  
Hydrogen Bond Acceptor ◽  
Continuous Generation ◽  
Relationship Model ◽  
Life Threatening ◽  
Molecular Modeling Studies ◽  
Resistant Strains ◽  
Imine Bond

Malaria is still a life-threatening public health issue, and the upsurge of resistant strains requires continuous generation of active molecules. In this work, 35 sulfonylhydrazone derivatives were synthesized and evaluated against Plasmodium falciparum chloroquine-sensitive (3D7) and resistant (W2) strains. The most promising compound, 5b, had an IC50 of 0.22 μM against W2 and was less cytotoxic and 26-fold more selective than chloroquine. The structure–activity relationship model, statistical analysis and molecular modeling studies suggested that antiplasmodial activity was related to hydrogen bond acceptor count, molecular weight and partition coefficient of octanol/water and displacement of frontier orbitals to the heteroaromatic ring beside the imine bond. This study demonstrates that the synthesized molecules with a simple scaffold allow the hit-to-lead process for new antimalarials to commence.

scholarly journals Antiplasmodial activity against resistant strains, toxicity and effect on mouse liver enzymes of extracts of Terminalia species found in Southwest Cameroon

2020 ◽  
Vol 10 (1) ◽  
pp. 132-138
Author(s):  
Moses Njutain Ngemenya ◽  
Grace Ntube Abwenzoh ◽  
Denis Zofou ◽  
Thierry Roland Kang ◽  
James Ajeck Mbah
Keyword(s):  
High Selectivity ◽  
Liver Enzymes ◽  
Antiplasmodial Activity ◽  
Leaf Extracts ◽  
Growth Inhibition Assay ◽  
Traditional Treatment ◽  
Methanol Extracts ◽  
Resistant Strains ◽  
Further Development

Introduction: Terminalia species have the potential to be exploited in phytomedicine based on their several pharmacological properties including antiplasmodial activity. However, there is need for more data on their antiplasmodial activity and toxicity. This study evaluated the antiplasmodial activities of Terminalia catappa and Terminalia superba found in the coastal area of Cameroon on resistant strains of Plasmodium falciparum not previously tested, and their toxicity. Methods: Three leaf extracts of each plant prepared separately using three organic solvents were screened in vitro on 3 strains of P. falciparum: chloroquine-sensitive 3D7, chloroquine-resistant Dd2 and multi-drug resistant W2mef using the parasite growth inhibition assay. Antiplasmodial activity was assessed using fluorescence microscopy and the parasite lactate dehydrogenase assay. Cytotoxicity of active extracts was assessed on LLC-MK2 monkey kidney epithelial cells and acute toxicity including effect on some liver enzymes in BALB/c mice. Results: The methanol extracts of both plants showed the highest antiplasmodial activity (IC50 between 5.03-9.76 μg/mL) on the three parasite strains. The methanol extracts showed high selectivity for parasites with selectivity index values ranging from 40 to 80 indicating very low risk of toxicity. There was no mortality or adverse effect and no significant effect on the liver enzymes, alanine aminotransferase (P = 0.506) and aspartate aminotransferase (P = 0.243). Conclusion: The antiplasmodial activity, high selectivity and no adverse effects for T. catappa and T. superba demonstrate the potential for use of these plants in traditional treatment of malaria, further development into a phytomedicine against malaria and as source of new antimalarial lead.

scholarly journals IN VITRO ANTIPLASMODIAL ACTIVITY OF FLOWER EXTRACTS FROM COMBRETUM LEPROSUM MART (MOFUMBO)

2016 ◽  
Vol 39 (1) ◽  
pp. 84 ◽  
Author(s):  
Guilherme Matos Passarini ◽  
Daniel Sol Medeiros ◽  
Dionatas Ulisses de Oliveira Meneguetti ◽  
Renato Abreu Lima ◽  
Valdir Alves Facundo ◽  
...  
Keyword(s):  
At Risk ◽  
Silica Gel ◽  
Column Chromatography ◽  
Chloroform Extract ◽  
Antiplasmodial Activity ◽  
Pharmacological Studies ◽  
Combretum Leprosum ◽  
Resistant Strains ◽  
Active Substances

Malaria is the cause of hundreds of deaths per year , besides putting billions of people at risk of developing disease. When it comes to its therapy, the drugs used currently are losing its efficacy due to increase inn the frequency of resistant strains of the parasite, highlight the importance for the serach of new classes of molecules prsentign antiplasmodial activity. In the present work, the antiplasmodial activities of five extracts from the flowers of Comretum leprosum are described. The method employed for obtaingine the extracts was silica gel column chromatography, and the techniques used for the analysis of antiplasmodial activity and citotoxicity were ELISA and MTT respectively, were a selectivitu index was calculated after the obtainign of these two values. The extract presenting the highest antiplasmodial activity was the chloroform extract, however, this extrac also presented the higther cytotoxicity and therefore the extract presenting the best overall activity was the hexane extract. The study deminstrated the plant Combretum leprosum has active substances against P. falciparum and therefore is a potential to be expored in funther pharmacological studies.

scholarly journals Synthesis, Molecular Docking and Antiplasmodial Activities of New Tetrahydro-β-Carbolines

2021 ◽  
Vol 22 (24) ◽  
pp. 13569
Author(s):  
Anna Jaromin ◽  
Beata Gryzło ◽  
Marek Jamrozik ◽  
Silvia Parapini ◽  
Nicoletta Basilico ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Molecular Docking ◽  
Molecular Modeling ◽  
Mechanism Of Action ◽  
Blood Cells ◽  
Antiplasmodial Activity ◽  
Drug Resistant ◽  
Human Red Blood Cells ◽  
Molecular Modeling Studies

Malaria is still one of the most dangerous infectious diseases and the emergence of drug resistant parasites only worsens the situation. A series of new tetrahydro-β-carbolines were designed, synthesized by the Pictet–Spengler reaction, and characterized. Further, the compounds were screened for their in vitro antiplasmodial activity against chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains of Plasmodium falciparum. Moreover, molecular modeling studies were performed to assess the potential action of the designed molecules and toxicity assays were conducted on the human microvascular endothelial (HMEC-1) cell line and human red blood cells. Our studies identified N-(3,3-dimethylbutyl)-1-octyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indole-3-carboxamide (7) (a mixture of diastereomers) as the most promising compound endowed with the highest antiplasmodial activity, highest selectivity, and lack of cytotoxicity. In silico simulations carried out for (1S,3R)-7 provided useful insights into its possible interactions with enzymes essential for parasite metabolism. Further studies are underway to develop the optimal nanosized lipid-based delivery system for this compound and to determine its precise mechanism of action.

scholarly journals Flavonoids as Potential anti-MRSA Agents through Modulation of PBP2a: A Computational and Experimental Study

Antibiotics ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 562 ◽  
Author(s):  
Hani A. Alhadrami ◽  
Ahmed A. Hamed ◽  
Hossam M. Hassan ◽  
Lassaad Belbahri ◽  
Mostafa E. Rateb ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Synergistic Effects ◽  
Binding Modes ◽  
Penicillin Binding Protein ◽  
Simulation Experiments ◽  
Life Threatening ◽  
Resistant Strains ◽  
Common Plant

Recently, the interest in plant-derived antimicrobial agents has increased. However, there are no sufficient studies dealing with their modes of action. Herein, we investigate an in-house library of common plant-based phenolic compounds for their potential antibacterial effects against the methicillin-resistant Staphylococcus aureus (MRSA), a widespread life-threatening superbug. Flavonoids, which are considered major constituents in the plant kingdom, were found to be a promising class of compounds against MRSA, particularly the non-glycosylated ones. On the other hand, the glycosylated derivatives, along with the flavonolignan silibinin A, were able to restore the inhibitory activity of ampicillin against MRSA. To explore the mode of action of this class, they were subjected to an extensive inverse virtual screening (IVS), which suggested penicillin-binding protein 2a (PBP2a) as a possible target that mediates both the antibacterial and the antibiotic-synergistic effects of this class of compounds. Further molecular docking and molecular dynamic simulation experiments were conducted to support the primary IVS and the in vitro results and to study their binding modes with PBP2a. Our findings shed a light on plant-derived natural products, notably flavonoids, as a promising and readily available source for future adjuvant antimicrobial therapy against resistant strains.

scholarly journals Multistage antiplasmodial activity of hydroxyethylamine compounds, in vitro and in vivo evaluations

RSC Advances ◽  
2020 ◽  
Vol 10 (58) ◽  
pp. 35516-35530
Author(s):  
Neha Sharma ◽  
Yash Gupta ◽  
Meenakshi Bansal ◽  
Snigdha Singh ◽  
Prateek Pathak ◽  
...  
Keyword(s):  
Human Population ◽  
Antiplasmodial Activity ◽  
Drug Resistant ◽  
Fast Growing ◽  
Resistant Strains ◽  
Global Threat ◽  
Drug Resistant Strains

Malaria, a global threat to the human population, remains a challenge partly due to the fast-growing drug-resistant strains of Plasmodium species.

scholarly journals Spread of Terbinafine-Resistant Trichophyton mentagrophytes Type VIII (India) in Germany–“The Tip of the Iceberg?”

2020 ◽  
Vol 6 (4) ◽  
pp. 207
Author(s):  
Pietro Nenoff ◽  
Shyam B. Verma ◽  
Andreas Ebert ◽  
Anke Süß ◽  
Eleni Fischer ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Substitution ◽  
Indian Subcontinent ◽  
Resistance Testing ◽  
Public Health Issue ◽  
Squalene Epoxidase ◽  
Amino Acid Substitutions ◽  
Type Viii ◽  
Resistant Strains

Chronic recalcitrant dermatophytoses, due to Trichophyton (T.) mentagrophytes Type VIII are on the rise in India and are noteworthy for their predominance. It would not be wrong to assume that travel and migration would be responsible for the spread of T. mentagrophytes Type VIII from India, with many strains resistant to terbinafine, to other parts of the world. From September 2016 until March 2020, a total of 29 strains of T. mentagrophytes Type VIII (India) were isolated. All patients were residents of Germany: 12 females, 15 males and the gender of the remaining two was not assignable. Patients originated from India (11), Pakistan (two), Bangladesh (one), Iraq (two), Bahrain (one), Libya (one) and other unspecified countries (10). At least two patients were German-born residents. Most samples (21) were collected in 2019 and 2020. All 29 T. mentagrophytes isolates were sequenced (internal transcribed spacer (ITS) and translation elongation factor 1-α gene (TEF1-α)). All were identified as genotype VIII (India) of T. mentagrophytes. In vitro resistance testing revealed 13/29 strains (45%) to be terbinafine-resistant with minimum inhibitory concentration (MIC) breakpoints ≥0.2 µg/mL. The remaining 16 strains (55%) were terbinafine-sensitive. Point mutation analysis revealed that 10/13 resistant strains exhibited Phe397Leu amino acid substitution of squalene epoxidase (SQLE), indicative for in vitro resistance to terbinafine. Two resistant strains showed combined Phe397Leu and Ala448Thr amino acid substitutions, and one strain a single Leu393Phe amino acid substitution. Out of 16 terbinafine-sensitive strains, in eight Ala448Thr, and in one Ala448Thr +, new Val444 Ile amino acid substitutions were detected. Resistance to both itraconazole and voriconazole was observed in three out of 13 analyzed strains. Treatment included topical ciclopirox olamine plus topical miconazole or sertaconazole. Oral itraconazole 200 mg twice daily for four to eight weeks was found to be adequate. Terbinafine-resistant T. mentagrophytes Type VIII are being increasingly isolated. In Germany, transmission of T. mentagrophytes Type VIII from the Indian subcontinent to Europe should be viewed as a significant public health issue.

scholarly journals Metallocene Antimalarials: The Continuing Quest

2008 ◽  
Vol 2008 ◽  
pp. 1-10 ◽  
Author(s):  
Margaret A. L. Blackie ◽  
Kelly Chibale
Keyword(s):  
Plasmodium Falciparum ◽  
Antiplasmodial Activity ◽  
Side Chain ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Resistant Strains ◽  
Antimalarial Compounds

Over the last decade, a significant body of research has been developed around the inclusion of a metallocene moiety into known antimalarial compounds. Ferroquine is the most successful of these compounds. Herein, we describe our contribution to metallocene antimalarials. Our approach has sought to introduce diversity sites in the side chain of ferroquine in order to develop a series of ferroquine derivatives. The replacement of the ferrocenyl moiety with ruthenocene has given rise to ruthenoquine and a modest series of analogues. The reaction of ferroquine and selected analogues with Au(PPh3)NO3, Au(C6F5)(tht), and [Rh(COD)Cl2] has resulted in a series of heterobimetallic derivatives. In all cases, compounds have been evaluated for in vitro antiplasmodial activity in both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. Preliminary structure-activity relationships have been delineated.

scholarly journals Efficacy of Colistin versus β-Lactams, Aminoglycosides, and Rifampin as Monotherapy in a Mouse Model of Pneumonia Caused by Multiresistant Acinetobacter baumannii

2002 ◽  
Vol 46 (6) ◽  
pp. 1946-1952 ◽  
Author(s):  
A. Montero ◽  
J. Ariza ◽  
X. Corbella ◽  
A. Doménech ◽  
C. Cabellos ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
In Vivo Model ◽  
Carbapenem Resistant ◽  
Bactericidal Efficacy ◽  
Life Threatening ◽  
Resistant Strains ◽  
Immunocompetent Mice ◽  
Moderately Resistant

ABSTRACT The treatment of life-threatening infections due to carbapenem-resistant Acinetobacter baumannii has become a serious challenge for physicians worldwide. Often, only colistin shows in general good in vitro activity against these carbapenem-resistant strains, but its antibacterial efficacy in comparison with the antibiotics most used in clinical practice is not well known. We studied the efficacy of colistin versus those of imipenem, sulbactam, tobramycin, and rifampin in an experimental pneumonia model with immunocompetent mice. We used three strains of A. baumannii corresponding to the main clones (A, D, and E) involved in the outbreaks of our hospital, with different grades of resistance to imipenem (imipenem MICs of 1, 8, and 512 μg/ml, respectively) and to the other antibiotics. The MIC of colistin was 0.5 μg/ml for the three strains. Reduction of log10 CFU/g in lung bacterial counts, clearance of bacteremia, and survival versus results with controls were used as parameters of efficacy. Imipenem and sulbactam (Δlung counts: −5.38 and −4.64 log10 CFU/ml) showed the highest level of bactericidal efficacy in infections by susceptible and even intermediate strains. Tobramycin and rifampin (−4.16 and −5.15 log10 CFU/ml) provided good results against intermediate or moderately resistant strains, in agreement with killing curves and pharmacodynamics. On the contrary, colistin showed the weakest antibacterial effect among the antibiotics tested, both in killing curves and in the in vivo model (−2.39 log10 CFU/ml; P < 0.05). We conclude that colistin did not appear as a good option for treatment of patients with pneumonia due to carbapenem-resistant A. baumannii strains. Other alternatives, including combinations with rifampin, may offer better therapeutic profiles and thus should be studied.

Mechanisms involved in effects of antimicrobial peptides, bactenectins ChBac3.4, ChBac5, and mini-ChBac7.5Nb, on bacterial cells

2017 ◽  
pp. 43-50
Author(s):  
О.В. Шамова ◽  
М.С. Жаркова ◽  
П.М. Копейкин ◽  
Д.С. Орлов ◽  
Е.А. Корнева
Keyword(s):  
Escherichia Coli ◽  
Antimicrobial Activity ◽  
Innate Immunity ◽  
Infectious Diseases ◽  
Metabolic Activity ◽  
Capra Hircus ◽  
Bacterial Cells ◽  
Antibiotic Resistant ◽  
Resistant Strains

Антимикробные пептиды (АМП) системы врожденного иммунитета - соединения, играющие важную роль в патогенезе инфекционных заболеваний, так как обладают свойством инактивировать широкий спектр патогенных бактерий, обеспечивая противомикробную защиту живых организмов. В настоящее время АМП рассматриваются как потенциальные соединения-корректоры инфекционной патологии, вызываемой антибиотикорезистентными бактериями (АБР). Цель данной работы состояла в изученим механизмов антибактериального действия трех пептидов, принадлежащих к семейству бактенецинов - ChBac3.4, ChBac5 и mini-ChBac7.5Nb. Эти химически синтезированные пептиды являются аналогами природных пролин-богатых АМП, обнаруженных в лейкоцитах домашней козы Capra hircus и проявляющих высокую антимикробную активность, в том числе и в отношении грамотрицательных АБР. Методы. Минимальные ингибирующие и минимальные бактерицидные концентрации пептидов (МИК и МБК) определяли методом серийных разведений в жидкой питательной среде с последующим высевом на плотную питательную среду. Эффекты пептидов на проницаемость цитоплазматической мембраны бактерий для хромогенного маркера исследовали с использованием генетически модифицированного штамма Escherichia coli ML35p. Действие бактенецинов на метаболическую активность бактерий изучали с применением маркера резазурина. Результаты. Показано, что все исследованные пептиды проявляют высокую антимикробную активность в отношении Escherichia coli ML35p и антибиотикоустойчивых штаммов Escherichia coli ESBL и Acinetobacter baumannii in vitro, но их действие на бактериальные клетки разное. Использован комплекс методик, позволяющих наблюдать в режиме реального времени динамику действия бактенецинов в различных концентрациях (включая их МИК и МБК) на барьерную функцию цитоплазматической мембраны и на интенсивность метаболизма бактериальных клеток, что дало возможность выявить различия в характере воздействия бактенецинов, отличающихся по структуре молекулы, на исследуемые микроорганизмы. Установлено, что действие каждого из трех исследованных бактенецинов в бактерицидных концентрациях отличается по эффективности нарушения целостности бактериальных мембран и в скорости подавления метаболизма клеток. Заключение. Полученная информация дополнит существующие фундаментальные представления о механизмах действия пролин-богатых пептидов врожденного иммунитета, а также послужит основой для биотехнологических исследований, направленных на разработку на базе этих соединений новых антибиотических препаратов для коррекции инфекционных заболеваний, вызываемых АБР и являющимися причинами тяжелых внутрибольничных инфекций. Antimicrobial peptides (AMPs) of the innate immunity are compounds that play an important role in pathogenesis of infectious diseases due to their ability to inactivate a broad array of pathogenic bacteria, thereby providing anti-microbial host defense. AMPs are currently considered promising compounds for treatment of infectious diseases caused by antibiotic-resistant bacteria. The aim of this study was to investigate molecular mechanisms of the antibacterial action of three peptides from the bactenecin family, ChBac3.4, ChBac5, and mini-ChBac7.5Nb. These chemically synthesized peptides are analogues of natural proline-rich AMPs previously discovered by the authors of the present study in leukocytes of the domestic goat, Capra hircus. These peptides exhibit a high antimicrobial activity, in particular, against antibiotic-resistant gram-negative bacteria. Methods. Minimum inhibitory and minimum bactericidal concentrations of the peptides (MIC and MBC) were determined using the broth microdilution assay followed by subculturing on agar plates. Effects of the AMPs on bacterial cytoplasmic membrane permeability for a chromogenic marker were explored using a genetically modified strain, Escherichia coli ML35p. The effect of bactenecins on bacterial metabolic activity was studied using a resazurin marker. Results. All the studied peptides showed a high in vitro antimicrobial activity against Escherichia coli ML35p and antibiotic-resistant strains, Escherichia coli ESBL and Acinetobacter baumannii, but differed in features of their action on bacterial cells. The used combination of techniques allowed the real-time monitoring of effects of bactenecin at different concentrations (including their MIC and MBC) on the cell membrane barrier function and metabolic activity of bacteria. The differences in effects of these three structurally different bactenecins on the studied microorganisms implied that these peptides at bactericidal concentrations differed in their capability for disintegrating bacterial cell membranes and rate of inhibiting bacterial metabolism. Conclusion. The obtained information will supplement the existing basic concepts on mechanisms involved in effects of proline-rich peptides of the innate immunity. This information will also stimulate biotechnological research aimed at development of new antibiotics for treatment of infectious diseases, such as severe in-hospital infections, caused by antibiotic-resistant strains.

Formulation and Evaluation of Mefloquine Hydrochloride Nanoparticles

2014 ◽  
Vol 7 (1) ◽  
pp. 2377-2386
Author(s):  
Dilip Kumar Gupta ◽  
B K Razdan ◽  
Meenakshi Bajpai
Keyword(s):  
Particle Size ◽  
Sustained Release ◽  
In Vitro Release ◽  
Entrapment Efficiency ◽  
Taste Masking ◽  
Diffusion Method ◽  
Drug Entrapment Efficiency ◽  
Resistant Strains ◽  
Vitro Release

The present study deals with the formulation and evaluation of mefloquine hydrochloride nanoparticles. Mefloquine is a blood schizonticidal quinoline compound, which is indicated for the treatment of mild-to-moderate acute malarial infections caused by mefloquine-susceptible multi-resistant strains of P. falciparum and P. vivax. The purpose of the present work is to minimize the dosing frequency, taste masking toxicity and to improve the therapeutic efficacy by formulating mefloquine HCl nanoparticles. Mefloquine nanoparticles were formulated by emulsion diffusion method using polymer poly(ε-caprolactone) with six different formulations. Nanoparticles were characterized by determining its particle size, polydispersity index, drug entrapment efficiency, drug content, particle morphological character and drug release. The particle size ranged between 100 nm to 240 nm. Drug entrapment efficacy was >95%. The in-vitro release of nanoparticles were carried out which exhibited a sustained release of mefloquine HCl from nanoparticles up to 24 hrs. The results showed that nanoparticles can be a promising drug delivery system for sustained release of mefloquine HCl.

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