scholarly journals Synthesis and Bioactivity of Phthalimide Analogs as Potential Drugs to Treat Schistosomiasis, a Neglected Disease of Poverty

2020 ◽  
Vol 13 (2) ◽  
pp. 25
Author(s):  
Snigdha Singh ◽  
Nelly El-Sakkary ◽  
Danielle E. Skinner ◽  
Prem Prakash Sharma ◽  
Sabine Ottilie ◽  
...  
Keyword(s):  
Hepg2 Cells ◽  
Developmental Stages ◽  
Surface Damage ◽  
New Drugs ◽  
Neglected Tropical Disease ◽  
Disease Treatment ◽  
Bioactive Scaffolds ◽  
Infective Larvae ◽  
Tegumental Surface ◽  
Blood Flukes

The neglected tropical disease, schistosomiasis, is caused by trematode blood flukes of the Schistosoma genus and infects approximately 200 million people worldwide. With just one partially effective drug available for disease treatment, new drugs are urgently needed. Herein, a series of 47 phthalimide (Pht) analogues possessing high-value bioactive scaffolds (i.e., benzimidazole and 1,2,3,-triazoles) was synthesized by click-chemistry. Compounds were evaluated for anti-schistosomal activity in culture against somules (post-infective larvae) and adults of Schistosoma mansoni, their predicted ADME (absorption, distribution, metabolism, and excretion) properties, and toxicity vs. HepG2 cells. The majority showed favorable parameters for surface area, lipophilicity, bioavailability and Lipinski score. Thirteen compounds were active at 10 µM against both somules and adults (6d, 6f, 6i–6l, 6n–6p, 6s, 6r’, 6t’ and 6w). Against somules, the majority caused degeneracy and/or death after 72 h; whereas against adult parasites, five compounds (6l, 6d, 6f, 6r’ and 6s) elicited degeneracy, tegumental (surface) damage and/or death. Strongest potency against both developmental stages was recorded for compounds possessing n-butyl or isobutyl as a linker, and a pentafluorophenyl group on triazole. Apart from five compounds for which anti-parasite activity tracked with toxicity to HepG2 cells, there was apparently no toxicity to HepG2 cells (EC50 values ≥50 µM). The data overall suggest that phthaloyl-triazole compounds are favorable synthons for additional studies as anti-schistosomals.

scholarly journals Three Alkaloids from an Apocynaceae Species, Aspidosperma spruceanum as Antileishmaniasis Agents by In Silico Demo-case Studies

Plants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 983 ◽  
Author(s):  
Diana Morales-Jadán ◽  
José Blanco-Salas ◽  
Trinidad Ruiz-Téllez ◽  
Francisco Centeno
Keyword(s):  
Free Energy ◽  
Active Site ◽  
In Silico ◽  
Binding Free Energy ◽  
New Drugs ◽  
Neglected Tropical Disease ◽  
Physiological Importance ◽  
Promising Tool ◽  
Binding Pockets ◽  
Simulation Results

This paper is focused on demonstrating with a real case that Ethnobotany added to Bioinformatics is a promising tool for new drugs search. It encourages the in silico investigation of “challua kaspi”, a medicinal kichwa Amazonian plant (Aspidosperma spruceanum) against a Neglected Tropical Disease, leishmaniasis. The illness affects over 150 million people especially in subtropical regions, there is no vaccination and conventional treatments are unsatisfactory. In attempts to find potent and safe inhibitors of its etiological agent, Leishmania, we recovered the published traditional knowledge on kichwa antimalarials and selected three A. spruceanum alkaloids, (aspidoalbine, aspidocarpine and tubotaiwine), to evaluate by molecular docking their activity upon five Leishmania targets: DHFR-TS, PTR1, PK, HGPRT and SQS enzymes. Our simulation results suggest that aspidoalbine interacts competitively with the five targets, with a greater affinity for the active site of PTR1 than some physiological ligands. Our virtual data also point to the demonstration of few side effects. The predicted binding free energy has a greater affinity to Leishmania proteins than to their homologous in humans (TS, DHR, PKLR, HGPRT and SQS), and there is no match with binding pockets of physiological importance. Keys for the in silico protocols applied are included in order to offer a standardized method replicable in other cases. Apocynaceae having ethnobotanical use can be virtually tested as molecular antileishmaniasis new drugs.

Antimicrobial Peptides: An Approach to Combat Resilient Infections

2020 ◽  
Vol 17 (4) ◽  
pp. 542-552 ◽  
Author(s):  
Debaprasad Parai ◽  
Pia Dey ◽  
Samir K. Mukherjee
Keyword(s):  
Antimicrobial Peptides ◽  
Developmental Stages ◽  
Rapid Development ◽  
Resistance Mechanisms ◽  
New Drugs ◽  
Bacterial Strains ◽  
Common People ◽  
Wide Range ◽  
Microbial Infections ◽  
Living Organisms

Background:It was apparent by the end of 1980s that the success against the threats of bacterial pathogens on public health was an illusion, with the rapid development of resistant strains more than the discovery of new drugs. As a consequence, the remedial services were in the backfoot position of being on the losing side of this never-ending evolutionary war. The quest for new antibiotics to overcome resistance problems has long been a top research priority for the researchers and the pharmaceutical industry. However, the resistance problems remain unresolved due to the abrupt misuse of antibiotics by common people, which has immensely worsened the scenario by disseminating antibiotic-resistant bacterial strains around the world.Objective:Thus, immediate action is needed to measure emerging and re-emerging microbial diseases having new resistance mechanisms and to manage their rapid spread among the common public by means of novel alternative metabolites.Conclusion:Antimicrobial Peptides (AMPs) are short, cationic peptides evolved in a wide range of living organisms and serve as the essential part of the host innate immunity. For humans, these effector molecules either can directly kill the foreign microbes or modulate the host immune systems so that the human body could develop some resistance against the microbial infections. In this review, we discuss their history, structural classifications, modes of action, and explain their biological roles as anti-infective agents. We also scrutinize their clinical potentiality, current limitations in various developmental stages and strategies to overcome for their successful clinical applications.

Herbal medicine: current progress, and challenges

2019 ◽  
Vol 15 ◽  
Author(s):  
Abul Barkat ◽  
Anjali Goyal ◽  
Abul Harshita ◽  
Faheem Hyder Pottoo ◽  
Sarwar Beg ◽  
...  
Keyword(s):  
Herbal Medicine ◽  
Capital Investment ◽  
Therapeutic Potential ◽  
Herbal Medicines ◽  
New Drugs ◽  
Disease Treatment ◽  
Late 20Th Century ◽  
Regulatory Standards ◽  
Medicine History ◽  
Regulatory Challenges

: Phytomedicine or herbal medicines have played an important role in disease treatment because of high therapeutic potential and better patient compliance. Although the practice of phytomedicne greatly affected during the dawn of the scientific era, there is a revival of interest in its potential by late 20th century, especially in the search of new drugs. Herbal drugs and its derivatives represent more than 50% of entire drugs in modern healthcare system. Because of the low success rate and huge capital investment hinders the further application of phytomedicine in disease treatment. In recent time, an increase of interest in the herbal meidicine has been observed by pharmaceutical industry to search novel phytotherapeutics. In the search of new phytomedicine there are several challenges identified like-the reproducibility of pharmacological activity of herbal extracts, toxicity and adverse effects, adulteration and contamination, herb–drug interactions issues; poor scientific and regulatory standards. In this review, we illustrated a short overview on herbal medicine history, current clinical perspective, pharmaceutical and regulatory challenges as well as its clinical presence. Moreover, problems encountered in drug discovery from herbal resources and its possible solutions are described.

Studies with Brugia pahangi 12. The activity of levamisole

1976 ◽  
Vol 50 (1) ◽  
pp. 21-28 ◽  
Author(s):  
Rosemary Rogers ◽  
D. A. Denham
Keyword(s):  
Aedes Aegypti ◽  
Developmental Stages ◽  
Brugia Pahangi ◽  
Infective Larvae ◽  
Vector Mosquito ◽  
Third Stage ◽  
Dose Levels

AbstractThe effects of levamisole on adults, third stage infective larvae, and microfilariae of Brugia pahangi were studied in in vitro culture and in vivo against developing stages in the vector mosquito and in infected cats. In vitro the drug was effective only at dose levels much higher than can be tolerated by mammals. It was active against the developmental stages of the worm in the vector Aedes aegypti.The drug was strongly microfilaricidal in cats but less effective against adult worms.

Onchocerca ochengi: morphological identification of the L3 in wild Simulium damnosum s.l., verified by DNA probes

Parasitology ◽  
1998 ◽  
Vol 116 (4) ◽  
pp. 337-348 ◽  
Author(s):  
G. WAHL ◽  
J. M. SCHIBEL
Keyword(s):  
Body Length ◽  
Developmental Stages ◽  
Infective Larva ◽  
Blot Hybridization ◽  
Dna Probe ◽  
Morphological Identification ◽  
Dot Blot ◽  
Infective Larvae ◽  
Simulium Damnosum ◽  
Onchocerca Ochengi

In order to assess the prevalence of the cattle filaria Onchocerca ochengi in onchocerciasis vectors (Simulium damnosum s.l.) in North Cameroon, we searched for a means to morphologically identify its developing larvae, which closely resemble those of O. volvulus. To this end microfilariae of the 2 Onchocerca species were isolated from slaughter cattle in Ngaoundéré and injected into neonate Simulium species. Whereas the early developmental stages (sausage stage, L2 and pre-infective larva) were indistinguishable, the infective larvae (L3) of O. ochengi were longer (median: 740 μm), more slender (diameter = 19·3 μm = 2·6% of body length) and had a relatively shorter tail (4·9% of body length) than those of O. volvulus (680 μm, 20·5 μm, 3·0% and 5·8% respectively). The tail of O. ochengi L3 was thick and rounded, whereas it was slightly tapering in O. volvulus L3. O. ochengi L3 produced by feeding flies on infected cattle in a different area in North Cameroon (Sora Mboum) showed the same features as intrathoracically produced O. ochengi L3 from Ngaoundéré, but were even longer (785 μm). On the basis of the differences in length, relative diameter, length of the tail and shape of the tail, a simple key for the separation of O. volvulus and O. ochengi L3 was elaborated, and 248 L3 found in wild S. damnosum s.l. were separated into ‘O. ochengi’ (160 L3) and ‘O. volvulus’ (88 L3) following this key. Sequential dot blot hybridization of each of the 248 larvae with a DNA probe which reacts with O. ochengi and O. volvulus but not with other Onchocerca species (pOo5/1) and with an O. volvulus-specific DNA probe (pOv12) revealed that the morphological identification had been correct in 86–91% of the cases. Only a small proportion (6–9%) of the dot blots did not react with either probe. Since this proportion was equal in experiments using experimentally produced L3 and in experiments using wild L3, the non-hybridization was certainly due to a loss of L3 during washing of the filters and not due to the presence of other unknown L3 species resembling O. volvulus and O. ochengi. Our study shows that in Cameroon it is possible to identify O. volvulus and O. ochengi infective larvae during routine fly dissections by morphology alone.

The transmission and development of Paracuaria adunca (Creplin, 1846) (Nematoda: Acuarioidea) of gulls (Laridae)

1982 ◽  
Vol 60 (12) ◽  
pp. 3092-3104 ◽  
Author(s):  
R. C. Anderson ◽  
P. L. Wong
Keyword(s):  
Carassius Auratus ◽  
Developmental Stages ◽  
Anser Anser ◽  
Culaea Inconstans ◽  
Semotilus Atromaculatus ◽  
Larval Stages ◽  
Infective Larvae ◽  
Goldfish Carassius Auratus ◽  
Breeding Grounds ◽  
Young Of The Year

Paracuaria adunca (Creplin, 1846) Anderson and Wong, 1981 of the gizzard of ring-billed gulls (Larus delawarensis Ord) developed to the infective stage in the amphipods Hyalella azteca, Crangonyx laurentianus, and Gammarus duebeni. At 18–20 °C the first moult occurred 10 days and the second 18 days postinfection. Worms developed in the proventriculus of experimentally infected gulls, the third moult occurred 2.5 days and the fourth 5 days postinfection. In 8 days immature adults were found under the gizzard lining near the proventriculus. Females found 16 days postinfection had larvated eggs. Developmental stages in amphipods and gulls are described. Prevalence and intensity of P. adunca were studied in adult and juvenile gulls at the Eastern Headland (Leslie Spit) of the Outer Toronto Harbour, Lake Ontario. The low mean intensity (1.6) in adult birds examined on April 2 suggests that there was little or no transmission of the parasite on the wintering grounds of the gulls. Intensity and prevalence increased in adult birds on the breeding grounds from April 2 to June 25 and larval stages were found in the birds. Prevalence in young-of-the-year birds increased with age of the birds. Intensity reached a high of 3.2 (1–6) in 35- to 42-day-old-birds (July 3). Infective larvae became encapsulated on the mesentery of experimentally infected goldfish (Carassius auratus). Infective larvae of P. adunca were found in the mesentery of fish (Culaea inconstans, Notropis hudsonius, Semotilus atromaculatus) collected in waters adjacent to the breeding grounds. Paracuaria adunca was transmitted experimentally to geese (Anser anser) and ducks (Anas platyrhynchos) but few worms were recovered from the few birds that became infected.

scholarly journals Novel therapies for acromegaly

2020 ◽  
Vol 9 (12) ◽  
pp. R274-R285
Author(s):  
Bernardo Maia ◽  
Leandro Kasuki ◽  
Mônica R Gadelha
Keyword(s):  
Medical Treatment ◽  
Disease Activity ◽  
Systemic Disease ◽  
New Drugs ◽  
Morbidity And Mortality ◽  
The Novel ◽  
Novel Therapies ◽  
Disease Treatment ◽  
Treatment Surgery

Acromegaly is a systemic disease associated with increased morbidity and mortality. Most of these comorbidities can be prevented or delayed with adequate disease treatment. Although three modalities of treatment (surgery, medical treatment, and radiotherapy) are available and new drugs were approved in the last decades, there are still some patients that maintain disease activity despite treatment. Therefore, there is a need for novel therapies for acromegaly and for that purpose new formulations of currently used drugs and also new drugs are currently under study. In this review, we summarize the novel therapies for acromegaly.

scholarly journals Molecular Modeling and Chemical Synthesis of New Safrol Oxime Ether Derivatives

2021 ◽  
Author(s):  
Mariana Silva ◽  
Marcia Veloso ◽  
Thaynan Chagas ◽  
Mirian Cordeiro ◽  
Levy Alves ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Molecular Targets ◽  
New Drugs ◽  
Public Health Issue ◽  
Neglected Tropical Disease ◽  
Cyclin Dependent Kinase ◽  
Covalent Bonds ◽  
High Affinity ◽  
High Degree ◽  
Affinity Profile

Leishmaniasis, a neglected tropical disease with a high worldwide incidence, is considered a public health issue in Minas Gerais and Brazil, with a high degree of morbidity, not to mention the lack of therapeutic arsenal. The cysteine protease (rCPB2.8) and cyclin dependent kinase (CRK3), important enzymes for the parasite’s feasibility, were the targets chosen for investigation of the new drugs. The following study aimed to analyze several oximic derivatives starting from safrol, which can present an affinity profile for selected molecular targets using tools from molecular modeling and bioinformatics, planning and synthesis of brand new substances being tested for leishmanicidal drugs. The study allowed to verify that three oximic derivatives (5a, 5f and 5h) presented high affinity for the CRK3 enzyme, and that the compounds 5c and 5g presented good interaction by the amino acids of the catalytic site of the rCPB2.8 enzyme with atomic distances capable of generating covalent bonds, which are essential for enzyme inhibitory activity.

scholarly journals (+)-Dehydrovomifoliol Alleviates Oleic Acid-Induced Lipid Accumulation in HepG2 Cells via the PPARα–FGF21 Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Yiyuan Xi ◽  
Jujia Zheng ◽  
Wei Xie ◽  
Xiangwei Xu ◽  
Namki Cho ◽  
...  
Keyword(s):  
Oleic Acid ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Lipid Accumulation ◽  
Hepg2 Cells ◽  
New Drugs ◽  
Acid Oxidation ◽  
Alcoholic Fatty Liver ◽  
Protein Levels ◽  
Artemisia Frigida

An overload of hepatic fatty acids, such as oleic acid is a key trigger of non-alcoholic fatty liver disease (NAFLD). Here, we investigated whether Artemisia frigida, a valuable traditional medicine used to treat various diseases, could mitigate OA-induced lipid accumulation in HepG2 cells. Then, to identify the active substances in A. frigida, a phytochemistry investigation was conducted using a bioassay-guided isolation method. Consequently, one terpene (1) and one flavone (2) were identified. Compound 1 ((+)-dehydrovomifoliol) exhibited potent effects against lipid accumulation in OA-induced HepG2 cells, without causing cyto-toxicity. Notably, treatment with (+)-dehydrovomifoliol decreased the expression levels of three genes related to lipogenesis (SREBP1, ACC, and FASN) and increased those of three genes related to fatty acid oxidation (PPARα, ACOX1, and FGF21). In addition, similar results were observed for SREBP1, PPARα, and FGF21 protein levels. The effects of (+)-dehydrovomifoliol were partially reversed by treatment with the PPARα antagonist GW6471, indicating the important role of the PPARα–FGF21 axis in the effects of (+)-dehydrovomifoliol. Based on its effects on hepatic lipogenesis and fatty acid oxidation signaling via the PPARα–FGF21 axis, (+)-dehydrovomifoliol isolated from A. frigida could be a useful early lead compound for developing new drugs for NAFLD prevention.

scholarly journals Anthelminthic effects of extracts of indigenous browses from mid rift valley of Ethiopia

2021 ◽  
Vol 25 (2) ◽  
pp. 132-143
Author(s):  
Amsalu Sisay ◽  
Tegene Negesse ◽  
Ajebu Nurfeta
Keyword(s):  
Developmental Stages ◽  
Negative Control ◽  
In Vitro Assays ◽  
Inhibition Assay ◽  
Egg Hatching ◽  
Acacia Senegal ◽  
Egg Hatch ◽  
Infective Larvae

This study was conducted to evaluate the potential anthelminthic properties of extracts of leaves of indigenous browses (Acacia seyal, Acacia senegal, Acacia tortilis, Millettia ferruginea, and Vernonia amygadalina) based on three in vitro assays. Acetone extracts of browses at different concentrations (75 to 1200 μg/ml, for egg and larvae and 100mg/ml for an adult) were tested on three developmental stages of Haemonchus contortus (eggs, infective larvae, and adult worms) using egg hatch assay (EHA), larval migration inhibition assay (LMIA) and adult worm motility inhibition assay (AMIA). Significant effects were obtained with all five browses but differences were observed depending on the parasitic stages. The effects of five browse extracts on egg hatching were concentration-dependent, the highest (P<0.05) egg hatch inhibition rate was observed at 1200 μg/ml concentration for all browses. All extracts had a higher effect (P<0.01) than that of the negative control, phosphate buffer saline (PBS). In contrast, no concentration-response relationship was found for infective larvae and adult worms, although more potent effects were observed with the highest concentrations. The LMI rate (70%) induced by Vernonia  amygadalina extract, at a concentration of 300 μg/ml, was the highest (P<0.05) of all other browses, even at higher concentrations. The highest LMI rate (62%) induced by Acacia senegal extract at higher concentration, was lower than that of LMI rate (70%) induced by Vernonia amygadalina, at 300 μg/ml concentration. Vernonia amygadalina was found to be highly and rapidly effective against adult worms inducing the highest mortality rate (90%) as soon as 4 hrs after incubation. Overall, the in vitro results suggest that these five  browses do possess anti-parasitic properties and Vernonia amygadalina showed the most effective anti-parasitic property. These effects remain to be confirmed through in vivo study.

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