scholarly journals 5-Phenoxy Primaquine Analogs and the Tetraoxane Hybrid as Antimalarial Agents

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3991
Author(s):  
Somruedee Jansongsaeng ◽  
Nitipol Srimongkolpithak ◽  
Jutharat Pengon ◽  
Sumalee Kamchonwongpaisan ◽  
Tanatorn Khotavivattana
Keyword(s):  
Drug Resistance ◽  
Mammalian Cells ◽  
Antimalarial Activity ◽  
Fold Increase ◽  
Hybrid Compound ◽  
Hybrid Strategy ◽  
Antimalarial Agents ◽  
Low Toxicity ◽  
Further Development ◽  
Rapid Emergence

The rapid emergence of drug resistance to the current antimalarial agents has led to the urgent need for the discovery of new and effective compounds. In this work, a series of 5-phenoxy primaquine analogs with 8-aminoquinoline core (7a–7h) was synthesized and investigated for their antimalarial activity against Plasmodium falciparum. Most analogs showed improved blood antimalarial activity compared to the original primaquine. To further explore a drug hybrid strategy, a conjugate compound between tetraoxane and the representative 5-phenoxy-primaquine analog 7a was synthesized. In our work, the hybrid compound 12 exhibited almost a 30-fold increase in the blood antimalarial activity (IC50 = 0.38 ± 0.11 μM) compared to that of primaquine, with relatively low toxicity against mammalian cells (SI = 45.61). Furthermore, we found that these 5-phenoxy primaquine analogs and the hybrid exhibit significant heme polymerization inhibition, an activity similar to that of chloroquine, which could contribute to their improved antimalarial activity. The 5-phenoxy primaquine analogs and the tetraoxane hybrid could serve as promising candidates for the further development of antimalarial agents.

Discovery of 3-Cinnamamido-N-Substituted Benzamides as Potential Antimalarial Agents

2020 ◽  
Vol 16 ◽  
Author(s):  
Haicheng Liu ◽  
Yushi Futamura ◽  
Honghai Wu ◽  
Aki Ishiyama ◽  
Taotao Zhang ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Antimalarial Activity ◽  
In Vitro Assays ◽  
Compound Library ◽  
Antimalarial Agents ◽  
Phenotypic Screen ◽  
Ic50 Values ◽  
Substituted Benzamides

Background: Malaria is one of the most devastating parasitic diseases, yet the discovery of antimalarial agents remains profoundly challenging. Very few new antimalarials have been developed in the past 50 years, while the emergence of drug-resistance continues to appear. Objective: This study focuses on the discovery, design, synthesis, and antimalarial evaluation of 3-cinnamamido-N-substituted benzamides. Method: In this study, a screening of our compound library was carried out against the multidrug-sensitive Plasmodium falciparum 3D7 strain. Derivatives of the hit were designed, synthesized and tested against P. falciparum 3D7 and the in vivo antimalarial activity of the most active compounds was evaluated using the method of Peters’ 4-day suppressive test. Results: The retrieved hit compound 1 containing a 3-cinnamamido-N-substituted benzamide skeleton showed moderate antimalarial activity (IC50 = 1.20 µM) for the first time. A series of derivatives were then synthesized through a simple four-step workflow, and half of them exhibited slightly better antimalarial effect than the precursor 1 during the subsequent in vitro assays. Additionally, compounds 11, 23, 30 and 31 displayed potent activity with IC50 values of approximately 0.1 µM, and weak cytotoxicity against mammalian cells. However, in vivo antimalarial activity is not effective which might be ascribed to the poor solubility of these compounds. Conclusion: In this study, phenotypic screen of our compound library resulted in the first report of 3-cinnamamide framework with antimalarial activity and 40 derivatives were then designed and synthesized. Subsequent structure-activity studies showed that compounds 11, 23, 30 and 31 exhibited the most potent and selective activity against P. falciparum 3D7 strain with IC50 values around 0.1 µM. Our work herein sets another example of phenotypic screen-based drug discovery, leading to potentially promising candidates of novel antimalarial agents once given further optimization.

scholarly journals Synthesis and Antimalarial Activities of Cyclen 4-Aminoquinoline Analogs

2009 ◽  
Vol 53 (4) ◽  
pp. 1320-1324 ◽  
Author(s):  
M. O. Faruk Khan ◽  
Mark S. Levi ◽  
Babu L. Tekwani ◽  
Shabana I. Khan ◽  
Eiichi Kimura ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
High Selectivity ◽  
Antimalarial Activity ◽  
New Class ◽  
Antimalarial Agents ◽  
Sensitive Clone ◽  
Resistant Strains ◽  
Incorporation Assay

ABSTRACT In an attempt to augment the efficacy of 7-chloro 4-aminoquinoline analogs and also to overcome resistance to antimalarial agents, we synthesized three cyclen (1,4,7,10-tetraazacyclododecane) analogs of chloroquine [a bisquinoline derivative, 7-chloro-4-(1,4,7,10-tetraaza-cyclododec-1-yl)-quinoline HBr, and a 7-chloro-4-(1,4,7,10-tetraaza-cyclododec-1-yl)-quinoline-Zn2+ complex]. The bisquinoline displays the most potent in vitro and in vivo antimalarial activities. It displays 50% inhibitory concentrations (IC50s) of 7.5 nM against the D6 (chloroquine-sensitive) clone of Plasmodium falciparum and 19.2 nM against the W2 (chloroquine-resistant) clone, which are comparable to those of artemisinin (10.6 and 5.0 nM, respectively) and lower than those of chloroquine (10.7 and 87.2 nM, respectively), without any evidence of cytotoxicity to mammalian cells, indicating a high selectivity index (>1,333 against D6 clone and >521 against W2 clone). Potent antimalarial activities of the bisquinoline against chloroquine- and mefloquine-resistant strains of P. falciparum were also confirmed by in vitro [3H]hypoxanthine incorporation assay. The in vivo antimalarial activity of the bisquinoline, as determined in P. berghei-infected mice, is comparable to that of chloroquine (50% effective dose, ≤1.1 mg/kg when given orally); no apparent toxicity has been observed up to the highest dose tested (3 × 30 mg/kg). The bisquinoline inhibits in vitro hemozoin (β-hematin) formation with an IC50 of 1.1 μM, which is about 10-fold more potent than chloroquine (IC50 9.5 μM). Overall, this article describes the discovery of a new class of cyclen 4-aminoquinoline analogs as potent antimalarial drugs.

scholarly journals Synthesis and Antiplasmodial Activity of Novel Fosmidomycin Derivatives and Conjugates with Artemisinin and Aminochloroquinoline

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4858 ◽  
Author(s):  
Despina Palla ◽  
Antonia I. Antoniou ◽  
Michel Baltas ◽  
Christophe Menendez ◽  
Philippe Grellier ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Infectious Diseases ◽  
Antimalarial Activity ◽  
Biological Evaluation ◽  
Antiplasmodial Activity ◽  
Malaria Parasites ◽  
Antimalarial Agents ◽  
New Compounds

Malaria, despite many efforts, remains among the most problematic infectious diseases worldwide, mainly due to the development of drug resistance by Plasmodium falciparum. The antibiotic fosmidomycin (FSM) is also known for its antimalarial activity by targeting the non-mevalonate isoprenoid synthesis pathway, which is essential for the malaria parasites but is absent in mammalians. In this study, we synthesized and evaluated against the chloroquine-resistant P. falciparum FcB1/Colombia strain, a series of FSM analogs, derivatives, and conjugates with other antimalarial agents, such as artemisinin (ART) and aminochloroquinoline (ACQ). The biological evaluation revealed four new compounds with higher antimalarial activity than FSM: two FSM-ACQ derivatives and two FSM-ART conjugates, with 3.5–5.4 and 41.5–23.1 times more potent activities than FSM, respectively.

The Evaluation of Metal Co-ordinating Bis-Thiosemicarbazones as Potential Anti-malarial Agents

2019 ◽  
Vol 15 (1) ◽  
pp. 51-58 ◽  
Author(s):  
Fady N. Akladios ◽  
Scott D. Andrew ◽  
Samantha J. Boog ◽  
Carmen de Kock ◽  
Richard K. Haynes ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
New Drugs ◽  
Preliminary Assessment ◽  
Human Lung Fibroblast ◽  
Antimalarial Agents ◽  
Fibroblast Line ◽  
Discrete Manner ◽  
Emergence Of Resistance ◽  
Further Development

Background:The emergence of resistance to the artemisinins which are the current mainstays for antimalarial chemotheraphy has created an environment where the development of new drugs acting in a mechanistally discrete manner is a priority.Objective:The goal of this work was to synthesize ane evaluate bis-thiosemicarbazones as potential antimalarial agents. </P><P> Methods: Fifteen compounds were generated using two condensation protocols and evaluated in vitro against the NF54 (CQ sensitive) strain of Plasmodium falciparum. A preliminary assessment of the potential for human toxicity was conducted in vitro against the MRC5 human lung fibroblast line.Results:The activity of the bis-thiosemicarbazones was highly dependent on the nature of the arene at the core of the structure. The inclusion of a non-coordinating benzene core resulted in inactive compounds, while the inclusion of a pyridyl core resulted in compounds of moderate or potent antimalarial activity (4 compounds showing IC50 < 250 nM).Conclusion:Bis-thiosemicarbazones containing a central pyridyl core display potent antimalarial activity in vitro. Sequestration and activation of ferric iron appears to play a significant role in this activity. Ongoing studies are aimed at further development of this series as potential antimalarials.

Low-toxicity carbon quantum dots derived from gentamicin sulfate to combat antibiotic resistance and eradicate mature biofilms

2020 ◽  
Vol 56 (15) ◽  
pp. 2316-2319 ◽  
Author(s):  
Peili Li ◽  
Shuai Liu ◽  
Weiwei Cao ◽  
Gaoke Zhang ◽  
Xu Yang ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Quantum Dots ◽  
Drug Resistance ◽  
Antibiotic Resistance ◽  
Mammalian Cells ◽  
Carbon Quantum Dots ◽  
Gentamicin Sulfate ◽  
Low Toxicity

Carbon quantum dots derived from gentamicin sulfate show low drug resistance, eradication of mature Staphylococcus aureus biofilm and low toxicity to mammalian cells.

Current insights into the chemistry and antitubercular potential of benzimidazole and imidazole derivatives

2020 ◽  
Vol 20 ◽  
Author(s):  
Deepa Parwani ◽  
Sushanta Bhattacharya ◽  
Akash Rathore ◽  
Chaitali Mallick ◽  
Vivek Asati ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Multi Drug Resistance ◽  
Benzimidazole Derivatives ◽  
Duration Of Treatment ◽  
Structure Activity ◽  
Mdr Tb ◽  
Low Toxicity ◽  
Extensively Drug Resistance ◽  
Improved Characteristics

: Tuberculosis is a disease caused by Mycobacterium tuberculosis (Mtb), affecting millions of people worldwide. The emergence of drug resistance is a major problem in the successful treatment of tuberculosis. Due to the commencement of MDR-TB (multi-drug resistance) and XDR-TB (extensively drug resistance), there is a crucial need for the development of novel anti-tubercular agents with improved characteristics such as low toxicity, enhanced inhibitory activity and short duration of treatment. In this direction, various heterocyclic compounds have been synthesized and screened against Mycobacterium tuberculosis. Among them, benzimidazole and imidazole containing derivatives found to have potential anti-tubercular activity. The present review focuses on various imidazole and benzimidazole derivatives (from 2015-2019) with their structure activity relationships in the treatment of tuberculosis.

Potential of Nanoparticles in Combating Candida Infections

2019 ◽  
Vol 16 (5) ◽  
pp. 478-491 ◽  
Author(s):  
Faizan Abul Qais ◽  
Mohd Sajjad Ahmad Khan ◽  
Iqbal Ahmad ◽  
Abdullah Safar Althubiani
Keyword(s):  
Targeted Delivery ◽  
Recent Progress ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Fold Increase ◽  
Antifungal Drugs ◽  
Low Toxicity ◽  
Candida Infections ◽  
Made In

Aims: The aim of this review is to survey the recent progress made in developing the nanoparticles as antifungal agents especially the nano-based formulations being exploited for the management of Candida infections. Discussion: In the last few decades, there has been many-fold increase in fungal infections including candidiasis due to the increased number of immunocompromised patients worldwide. The efficacy of available antifungal drugs is limited due to its associated toxicity and drug resistance in clinical strains. The recent advancements in nanobiotechnology have opened a new hope for the development of novel formulations with enhanced therapeutic efficacy, improved drug delivery and low toxicity. Conclusion: Metal nanoparticles have shown to possess promising in vitro antifungal activities and could be effectively used for enhanced and targeted delivery of conventionally used drugs. The synergistic interaction between nanoparticles and various antifungal agents have also been reported with enhanced antifungal activity.

Antifungal Activity Directed Toward the Cell Wall by 2-Cyclohexylidenhydrazo- 4-Phenyl-Thiazole Against Candida albicans

2019 ◽  
Vol 19 (4) ◽  
pp. 428-438 ◽  
Author(s):  
Nívea P. de Sá ◽  
Ana P. Pôssa ◽  
Pilar Perez ◽  
Jaqueline M.S. Ferreira ◽  
Nayara C. Fonseca ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Antifungal Activity ◽  
Mammalian Cells ◽  
C Elegans ◽  
Buccal Epithelial Cells ◽  
Mutant Strains ◽  
Low Toxicity ◽  
High Concentrations ◽  
Mic Value

<p>Background: The increasing incidence of invasive forms of candidiasis and resistance to antifungal therapy leads us to seek new and more effective antifungal compounds. </P><P> Objective: To investigate the antifungal activity and toxicity as well as to evaluate the potential targets of 2- cyclohexylidenhydrazo-4-phenyl-thiazole (CPT) in Candida albicans. </P><P> Methods: The antifungal activity of CPT against the survival of C. albicans was investigated in Caenorhabditis elegans. Additionally, we determined the effect of CPT on the inhibition of C. albicans adhesion capacity to buccal epithelial cells (BECs), the toxicity of CPT in mammalian cells, and the potential targets of CPT in C. albicans. </P><P> Results: CPT exhibited a minimum inhibitory concentration (MIC) value of 0.4-1.9 µg/mL. Furthermore, CPT at high concentrations (>60 x MIC) showed no or low toxicity in HepG2 cells and <1% haemolysis in human erythrocytes. In addition, CPT decreased the adhesion capacity of yeasts to the BECs and prolonged the survival of C. elegans infected with C. albicans. Analysis of CPT-treated cells showed that their cell wall was thinner than that of untreated cells, especially the glucan layer. We found that there was a significantly lower quantity of 1,3-β-D-glucan present in CPT-treated cells than that in untreated cells. Assays performed on several mutant strains showed that the MIC value of CPT was high for its antifungal activity on yeasts with defective 1,3-β-glucan synthase. </P><P> Conclusion: In conclusion, CPT appears to target the cell wall of C. albicans, exhibits low toxicity in mammalian cells, and prolongs the survival of C. elegans infected with C. albicans.</p>

scholarly journals 1186. Cefazolin inoculum effect predicts reduced susceptibility to other antibiotics and patient outcomes in MSSA endovascular infections

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S617-S617
Author(s):  
Dan Smelter ◽  
Sue McCrone ◽  
Warren Rose
Keyword(s):  
Infective Endocarditis ◽  
Mortality Rate ◽  
Patient Outcomes ◽  
Treatment Options ◽  
Fold Increase ◽  
Specific Mechanism ◽  
Research Support ◽  
High Burden ◽  
Low Toxicity ◽  
Inoculum Effect

Abstract Background MSSA Infective endocarditis (IE) is inherently a high-burden infection with up to a 30% mortality rate. Cefazolin is an appealing treatment option for IE with low toxicity and a favorable dosing scheme. However, cefazolin has been associated with treatment failure in IE, attributed to an inoculum effect. The specific mechanism underlying the cefazolin inoculum effect (CIE) remains undetermined, but CIE has been linked to both blaZ expression and agr dysfunction. This study aims to determine whether CIE is linked to reduced susceptibility to other antibiotics and worse outcomes regardless of therapy in MSSA endovascular infections. Methods Sixty-four MSSA strains were collected from patients with endovascular infections not treated with cefazolin. To determine CIE phenotype, strains were cultured and MICs assayed for cefazolin, nafcillin, and vancomycin at 107 CFU/mL for high-inocula (HI) and 105 CFU/mL for standard-inocula (SI). This study defined CIE as a ≥ 4-fold increase in MIC at HI compared to SI, with at least an MIC of 4 mg/L at HI. Nitrocefin disks identified blaZ expression, and beta lysin disks were used to determine hemolysin type and agr function. Patient outcomes of mortality and bacteremia duration were assessed across cohorts. Results Twenty-four strains exhibit a CIE (38%), with 10 strains having an MIC of ≥ 32mg/L at HI. Nafcillin and vancomycin also had an inoculum effect, uncoupled from the CIE and occurring at a lower frequency and amplitude at HI. Presence of CIE had a greater association with blaZ expression (71% vs 25%) than agr dysfunction (38% vs 20%). 50% (9/18) of CIE infections were cleared within 48 hours while 77% (20/26) of CIE-negative infections were cleared within 48 hours (P=0.106). However, presence of CIE was not associated with increased mortality (25% CIE-positive vs 35%; P=0.578) Conclusion Previous studies for CIE failed to enrich for isolates from endovascular sources, where inocula are known to be high. This study presents one of the largest endovascular source cohorts for CIE evaluation. It identifies that CIE prevalence (38%) is higher than reports from diverse infection sources (10-36%). CIE appears to predict bacteremia duration with other MSSA treatment options, suggesting mechanisms independent of blaZ and agr function for this phenomenon. Disclosures Warren Rose, PharmD, MPH, Merck (Grant/Research Support)Paratek (Grant/Research Support)

scholarly journals Functionalized Chitosan Nanomaterials: A Jammer for Quorum Sensing

Polymers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 2533
Author(s):  
Moupriya Nag ◽  
Dibyajit Lahiri ◽  
Dipro Mukherjee ◽  
Ritwik Banerjee ◽  
Sayantani Garai ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Quorum Sensing ◽  
Targeted Delivery ◽  
Direct Interaction ◽  
Orthodontic Appliances ◽  
Chronic Infections ◽  
Functionalized Nanomaterials ◽  
Low Toxicity ◽  
Novel Target ◽  
Positively Charged

The biggest challenge in the present-day healthcare scenario is the rapid emergence and spread of antimicrobial resistance due to the rampant use of antibiotics in daily therapeutics. Such drug resistance is associated with the enhancement of microbial virulence and the acquisition of the ability to evade the host’s immune response under the shelter of a biofilm. Quorum sensing (QS) is the mechanism by which the microbial colonies in a biofilm modulate and intercept communication without direct interaction. Hence, the eradication of biofilms through hindering this communication will lead to the successful management of drug resistance and may be a novel target for antimicrobial chemotherapy. Chitosan shows microbicidal activities by acting electrostatically with its positively charged amino groups, which interact with anionic moieties on microbial species, causing enhanced membrane permeability and eventual cell death. Therefore, nanoparticles (NPs) prepared with chitosan possess a positive surface charge and mucoadhesive properties that can adhere to microbial mucus membranes and release their drug load in a constant release manner. As the success in therapeutics depends on the targeted delivery of drugs, chitosan nanomaterial, which displays low toxicity, can be safely used for eradicating a biofilm through attenuating the quorum sensing (QS). Since the anti-biofilm potential of chitosan and its nano-derivatives are reported for various microorganisms, these can be used as attractive tools for combating chronic infections and for the preparation of functionalized nanomaterials for different medical devices, such as orthodontic appliances. This mini-review focuses on the mechanism of the downregulation of quorum sensing using functionalized chitosan nanomaterials and the future prospects of its applications.

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