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Artemisinin resistance

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https://www.readbyqxmd.com/read/29326018/semisynthesis-cytotoxicity-antimalarial-evaluation-and-structure-activity-relationship-of-two-series-of-triterpene-derivatives
#1
Simone Tasca Cargnin, Andressa Finkler Staudt, Patrícia Medeiros, Daniel de Medeiros Sol Sol, Ana Paula de Azevedo Dos Santos, Fernando Berton Zanchi, Grace Gosmann, Antonio Puyet, Carolina Bioni Garcia Teles, Simone Baggio Gnoatto
In this report, we describe the semisynthesis of two series of ursolic and betulinic acid derivatives through designed by modifications at the C-3 and C-28 positions and demonstrate their antimalarial activity against chloroquine-resistant P. falciparum (W2 strain). Structural modifications at C-3 were more advantageous to antimalarial activity than simultaneous modifications at C-3 and C-28 positions. The ester derivative, 3β-butanoyl betulinic acid (7b), was the most active compound (IC50 = 3.4 µM) and it did not exhibit cytotoxicity against VERO nor HepG2 cells (CC50 > 400 µM), showing selectivity towards parasites (selectivity index > 117...
December 29, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29320822/antimalarial-activity-of-c-10-substituted-triazolyl-artemisinin
#2
Gab-Man Park, Hyun Park, Sangtae Oh, Seokjoon Lee
We synthesized C-10 substituted triazolyl artemisinins by the Huisgen cycloaddition reaction between dihydroartemisinins (2) and variously substituted 1, 2, 3-triazoles (8a-8h). The antimalarial activities of 32 novel artemisinin derivatives were screened against a chloroquine-resistant parasite. Among them, triazolyl artemisinins with electron-withdrawing groups showed stronger antimalarial activities than those shown by the derivatives having electron-donating groups. In particularly, m-chlorotriazolyl artemisinin (9d-12d) showed antimalarial activity equivalent to that of artemisinin and could be a strong drug candidate...
December 2017: Korean Journal of Parasitology
https://www.readbyqxmd.com/read/29320160/efforts-aimed-to-reduce-attrition-in-antimalarial-drug-discovery-a-systematic-evaluation-of-current-antimalarial-targets-portfolio
#3
María Jesus Chaparro, Felix Calderon, Pablo Castañeda, Elena Fernandez Alvaro, Raquel Gabarro, Francisco-Javier Gamo, María G Gómez-Lorenzo, Julio Martín, Esther Fernandez
Malaria remains a major global health problem. In 2015 alone, more than 200 million cases of malaria were reported, and more than 400,000 deaths occurred. Since 2010, emerging resistance to current front-line ACTs (Artemisinin Combination Therapies) has been detected in endemic countries. Therefore, there is an urgency for new therapies based on novel modes of action, able to relieve symptoms as fast as the artemisinins and/or block malaria transmission. During the past few years, the antimalarial community has focused their efforts on phenotypic screening as a pragmatic approach to identify new hits...
January 10, 2018: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29317166/synthesis-in-vitro-antimalarial-activities-and-cytotoxicities-of-amino-artemisinin-ferrocene-derivatives
#4
Christo de Lange, Dina Coertzen, Frans J Smit, Johannes F Wentzel, Ho Ning Wong, Lyn-Marie Birkholtz, Richard K Haynes, David D N'Da
Novel derivatives bearing a ferrocene attached via a piperazine linker to C-10 of the artemisinin nucleus were prepared from dihydroartemisinin and screened against chloroquine (CQ) sensitive NF54 and CQ resistant K1 and W2 strains of Plasmodium falciparum (Pf) parasites. The overall aim is to imprint oxidant (from the artemisinin) and redox (from the ferrocene) activities. In a preliminary assessment, these compounds were shown to possess activities in the low nM range with the most active being compound 6 with IC50 values of 2...
December 26, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29301383/increasing-the-strength-and-production-of-artemisinin-and-its-derivatives
#5
REVIEW
Syed Lal Badshah, Asad Ullah, Nasir Ahmad, Zainab M Almarhoon, Yahia Mabkhot
Artemisinin is a natural sesquiterpene lactone obtained from the Artemisia annua herb. It is widely used for the treatment of malaria. In this article, we have reviewed the role of artemisinin in controlling malaria, spread of resistance to artemisinin and the different methods used for its large scale production. The highest amount of artemisinin gene expression in tobacco leaf chloroplast leads to the production of 0.8 mg/g of the dry weight of the plant. This will revolutionize the treatment and control of malaria in third world countries...
January 3, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29281988/intravenous-artesunate-plus-artemisnin-based-combination-therapy-act-or-intravenous-quinine-plus-act-for-treatment-of-severe-malaria-in-ugandan-children-a-randomized-controlled-clinical-trial
#6
Pauline Byakika-Kibwika, Jane Achan, Mohammed Lamorde, Carine Karera-Gonahasa, Agnes N Kiragga, Harriet Mayanja-Kizza, Noah Kiwanuka, Sam Nsobya, Ambrose O Talisuna, Concepta Merry
BACKGROUND: Severe malaria is a medical emergency associated with high mortality. Adequate treatment requires initial parenteral therapy for fast parasite clearance followed by longer acting oral antimalarial drugs for cure and prevention of recrudescence. METHODS: In a randomized controlled clinical trial, we evaluated the 42-day parasitological outcomes of severe malaria treatment with intravenous artesunate (AS) or intravenous quinine (QNN) followed by oral artemisinin based combination therapy (ACT) in children living in a high malaria transmission setting in Eastern Uganda...
December 28, 2017: BMC Infectious Diseases
https://www.readbyqxmd.com/read/29280424/treatment-seeking-behavior-after-the-implementation-of-a-unified-policy-of-dihydroartemisinin-piperaquine-for-the-treatment-of-uncomplicated-malaria-in-papua-indonesia
#7
Angela Devine, Enny Kenangalem, Lenny Burdarm, Nicholas M Anstey, Jeanne Rini Poespoprodjo, Ric N Price, Shunmay Yeung
Artemisinin combination therapy is recommended for the treatment of multidrug resistant Plasmodium falciparum and Plasmodium vivax. In March 2006, antimalarial policy in Indonesia was changed to a unified treatment with dihydroartemisinin-piperaquine for all species of malaria because of the low efficacy of previous drug treatments. In 2013, a randomized cross-sectional household survey in Papua was used to collect data on demographics, parasite positivity, treatment-seeking behavior, diagnosis and treatment of malaria, and household costs...
December 26, 2017: American Journal of Tropical Medicine and Hygiene
https://www.readbyqxmd.com/read/29280362/overview-of-the-improvement-of-the-ring-stage-survival-assay-a-novel-phenotypic-assay-for-the-detection-of-artemisinin-resistant-plasmodium-falciparum
#8
REVIEW
Jie Zhang, Guo-Hua Feng, Chun-Yan Zou, Pin-Can Su, Huai-E Liu, Zhao-Qing Yang
Artemisinin resistance in Plasmodium falciparum threatens the remarkable efficacy of artemisinin-based combination therapies worldwide. Thus, greater insight into the resistance mechanism using monitoring tools is essential. The ring-stage survival assay is used for phenotyping artemisinin-resistance or decreased artemisinin sensitivity. Here, we review the progress of this measurement assay and explore its limitations and potential applications.
November 18, 2017: Zoological Research
https://www.readbyqxmd.com/read/29260689/drug-resistant-polymorphisms-and-copy-numbers-in-plasmodium-falciparum-mozambique-2015
#9
Himanshu Gupta, Eusebio Macete, Helder Bulo, Crizolgo Salvador, Marian Warsame, Eva Carvalho, Didier Ménard, Pascal Ringwald, Quique Bassat, Sonia Enosse, Alfredo Mayor
One of the fundamental steps toward malaria control is the use of antimalarial drugs. The success of antimalarial treatment can be affected by the presence of drug-resistant populations of Plasmodium falciparum. To assess resistance, we used molecular methods to examine 351 P. falciparum isolates collected from 4 sentinel sites in Mozambique for K13, pfmdr1, pfcrt, and pfdhps polymorphisms and for plasmepsin2 (pfpm2) and pfmdr1 copy numbers. We found multiple copies of pfpm2 in 1.1% of isolates. All isolates carried K13 wild-type alleles (3D7-like), except 4 novel polymorphisms (Leu619Leu, Phe656Ile, Val666Val, Gly690Gly)...
January 2018: Emerging Infectious Diseases
https://www.readbyqxmd.com/read/29258508/functional-analysis-of-plasmodium-falciparum-subpopulations-associated-with-artemisinin-resistance-in-cambodia
#10
Ankit Dwivedi, Christelle Reynes, Axel Kuehn, Daniel B Roche, Nimol Khim, Maxim Hebrard, Sylvain Milanesi, Eric Rivals, Roger Frutos, Didier Menard, Choukri Ben Mamoun, Jacques Colinge, Emmanuel Cornillot
BACKGROUND: Plasmodium falciparum malaria is one of the most widespread parasitic infections in humans and remains a leading global health concern. Malaria elimination efforts are threatened by the emergence and spread of resistance to artemisinin-based combination therapy, the first-line treatment of malaria. Promising molecular markers and pathways associated with artemisinin drug resistance have been identified, but the underlying molecular mechanisms of resistance remains unknown...
December 19, 2017: Malaria Journal
https://www.readbyqxmd.com/read/29246208/when-it-just-won-t-go-away-oral-artemisinin-monotherapy-in-nigeria-threatening-lives-threatening-progress
#11
Chinazo Ujuju, Jennifer Anyanti, Paul N Newton, Godwin Ntadom
BACKGROUND: Oral artemisinin monotherapy (AMT), an important contributor to multi-drug resistant malaria, has been banned in Nigeria. While oral AMT has scarcely been found for several years now in other malaria-endemic countries, availability has persisted in Nigeria's private sector. In 2015, the ACTwatch project conducted a nationally representative outlet survey. Results from the outlet survey show the extent to which oral AMT prevails in Nigeria's anti-malarial market, and provide key product information to guide strategies for removal...
December 15, 2017: Malaria Journal
https://www.readbyqxmd.com/read/29241036/plasmodium-peekaboo-pk4-mediates-parasite-latency
#12
Edward Rea, Anthony A Holder, Rita Tewari
In this issue of Cell Host & Microbe, Zhang et al. (2017) show that translational repression through eIF2α phosphorylation mediated by PK4 kinase activity plays a key role in artemisinin resistance in recrudescent malaria infections. Targeting this druggable process could extend the lifespan of current frontline treatments.
December 13, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/29229871/antifolate-drug-resistance-novel-mutations-and-haplotype-distribution-in-dhps-and-dhfr-from-northeast-india
#13
N P Sarmah, K Sarma, D R Bhattacharyya, A A Sultan, D Bansal, N Singh, P K Bharti, R Sehgal, P K Mohapatra, P Parida, J Mahanta
Malaria is a major public health concern in Northeast India with a preponderance of drug-resistant strains. Until recently the partner drug for artemisinin combination therapy (ACT) was sulphadoxine pyrimethamine (SP). Antifolate drug resistance has been associated with the mutations at dihydropteroate synthase (dhps) and dihydrofolatereductase (dhfr) genes. This study investigated antifolate drug resistance at the molecular level. A total of 249 fever cases from Arunachal Pradesh, NE India, were screened for malaria, and of these, 75 were found to be positive for Plasmodium falciparum...
December 2017: Journal of Biosciences
https://www.readbyqxmd.com/read/29219249/activities-of-11-azaartemisinin-and-n-sulfonyl-derivatives-against-asexual-and-transmissible-malaria-parasites
#14
Rozanne Harmse, Dina Coertzen, Ho Ning Wong, Frans J Smit, Mariette E van der Watt, Janette Reader, Sindiswe H Nondaba, Lyn-Marie Birkholtz, Richard K Haynes, David D N'Da
Dihydroartemisinin (DHA), either used in its own right or as the active drug generated in vivo from the other artemisinins in current clinical use-artemether and artesunate-induces quiescence in ring-stage parasites of Plasmodium falciparum (Pf). This induction of quiescence is linked to artemisinin resistance. Thus, we have turned to structurally disparate artemisinins that are incapable of providing DHA on metabolism. Accordingly, 11-azaartemisinin 5 and selected N-sulfonyl derivatives were screened against intraerythrocytic asexual stages of drug-sensitive Pf NF54 and drug-resistant K1 and W2 parasites...
December 8, 2017: ChemMedChem
https://www.readbyqxmd.com/read/29215279/design-and-synthesis-of-orally-bioavailable-piperazine-substituted-4-1h-quinolones-with-potent-antimalarial-activity-structure-activity-and-structure-property-relationship-studies
#15
Raghupathi Neelarapu, Jordany R Maignan, Cynthia L Lichorowic, Andrii Monastyrskyi, Tina S Mutka, Alexis N LaCrue, Lynn D Blake, Debora Casandra, Sherwin Mashkouri, Jeremy N Burrows, Paul A Willis, Dennis E Kyle, Roman Manetsch
Malaria deaths have been decreasing over the last 10-15 years, with global mortality rates having fallen by 47% since 2000. While the World Health Organization (WHO) recommends the use of artemisinin-based combination therapies (ACTs) to combat malaria, the emergence of artemisinin resistant strains underscores the need to develop new antimalarial drugs. Recent in vivo efficacy improvements of the historical antimalarial ICI 56,780 have been reported, however with the poor solubility and rapid development of resistance, this compound requires further optimization...
December 7, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29213208/awareness-of-malaria-and-treatment-seeking-behaviour-among-persons-with-acute-undifferentiated-fever-in-the-endemic-regions-of-myanmar
#16
Phyo Aung Naing, Thae Maung Maung, Jaya Prasad Tripathy, Tin Oo, Khin Thet Wai, Aung Thi
Background: Myanmar has a high burden of malaria with two-third of the population at risk of malaria. One of the basic elements of the Roll Back Malaria Initiative to fight against malaria is early diagnosis and treatment within 24 h of fever. Public awareness about malaria is a key factor in malaria prevention and control and in improving treatment-seeking behaviour. Methods: A large community-based survey was carried out in 27 townships of malaria endemic regions in Myanmar in 2015 which reported on the knowledge, behaviour and practices around malaria in the general population...
2017: Tropical Medicine and Health
https://www.readbyqxmd.com/read/29194347/in-vivo-and-in-vitro-activities-and-adme-tox-profile-of-a-quinolizidine-modified-4-aminoquinoline-a-potent-anti-p-falciparum-and-anti-p-vivax-blood-stage-antimalarial
#17
Nicoletta Basilico, Silvia Parapini, Anna Sparatore, Sergio Romeo, Paola Misiano, Livia Vivas, Vanessa Yardley, Simon L Croft, Annette Habluetzel, Leonardo Lucantoni, Laurent Renia, Bruce Russell, Rossarin Suwanarusk, Francois Nosten, Giulio Dondio, Chiara Bigogno, Daniela Jabes, Donatella Taramelli
Natural products are a prolific source for the identification of new biologically active compounds. In the present work, we studied the in vitro and in vivo antimalarial efficacy and ADME-Tox profile of a molecular hybrid (AM1) between 4-aminoquinoline and a quinolizidine moiety derived from lupinine (Lupinus luteus). The aim was to find a compound endowed with the target product profile-1 (TCP-1: molecules that clear asexual blood-stage parasitaemia), proposed by the Medicine for Malaria Venture to accomplish the goal of malaria elimination/eradication...
December 1, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29193799/preliminary-evaluation-of-artemisinin-cholesterol-conjugates-as-potential-drugs-for-treatment-of-intractable-forms-of-malaria-and-tuberculosis
#18
Mokhitli Morake, Dina Coertzen, Andile Ngwane, Johannes Wentzel, Ho Ning Wong, Frans Smit, Lyn-Marie Birkholtz, Ray-Dean Petersen, Bienyameen Baker, Ian Wiid, David N'Da, Richard K Haynes
In order to evaluate the feasibility of developing drugs that may be active against both malaria and tuberculosis (TB) by utilizing in part putative cholesterol transporters in the causative pathogens and through enhancement of passive diffusion in granulomatous TB, artemisinin-cholesterol conjugates were synthesized by connecting the component molecules through various linkers. The compounds were screened in vitro against Plasmodium falciparum (Pf) and Mycobacterium tuberculosis (Mtb). Antimalarial activities (IC50) against Pf drug sensitive NF54, and drug resistant K1 and W2 strains ranged from 0...
November 28, 2017: ChemMedChem
https://www.readbyqxmd.com/read/29192183/prevalence-of-mutations-linked-to-antimalarial-resistance-in-plasmodium-falciparum-from-chhattisgarh-central-india-a-malaria-elimination-point-of-view
#19
Priyanka Patel, Praveen K Bharti, Devendra Bansal, Nazia A Ali, Rajive K Raman, Pradyumna K Mohapatra, Rakesh Sehgal, Jagadish Mahanta, Ali A Sultan, Neeru Singh
Antimalarial drug resistance is a major global challenge in malaria control and elimination. Mutations in six different genes of Plasmodium falciparum (crt, mdr1, dhfr, dhps, ATPase6 and K-13 propeller) that confer resistance to chloroquine, sulphadoxine-pyrimethamine and artemisinin-based combination therapy were analyzed in samples from Chhattisgarh. Seventy-eight percent of the samples were found to have a pfcrt mutation (53% double, 24% triple and 1% single mutant), and 59% of pfmdr1 genes were found to have an N86Y mutation...
November 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29185748/4-aminoquinoline-antimalarials-containing-a-benzylmethylpyridylmethylamine-group-are-active-against-drug-resistant-plasmodium-falciparum-and-exhibit-oral-activity-in-mice
#20
Mukesh C Joshi, John Okombo, Samkele Nsumiwa, Jeffrey Ndove, Dale Taylor, Lubbe Wiesner, Roger Hunter, Kelly Chibale, Timothy J Egan
Emergence of drug resistant Plasmodium falciparum including artemisinin-tolerant parasites highlights the need for new antimalarials. We have previously shown that dibemequines, 4-amino-7-chloroquinolines with dibenzylmethylamine (dibemethin) side chains, are efficacious. In this study, analogues in which the terminal phenyl group of the dibemethin was replaced with a 2-pyridyl group and the 4-amino-7-chloroquinoline was either maintained or replaced with a 4-aminoquinoline-7-carbonitrile were synthesized in an effort to improve drug-likeness...
November 29, 2017: Journal of Medicinal Chemistry
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