Diversity-oriented synthesis derived indole based spiro and fused small molecules kills artemisinin-resistant Plasmodium falciparum.
Akshaykumar Nayak,Himani Saxena,Chandramohan Bathula,Tarkeshwar Kumar,Souvik Bhattacharjee,Subhabrata Sen,Ashish Gupta +6 more
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TLDR
1-aryltetrahydro-β-carbolines 2 and 3 shows promising anti-plasmodial activity that can kill both artemisinin-sensitive and artemis inin-resistant strains of P. falciparum.Abstract:
Despite numerous efforts to eradicate the disease, malaria continues to remain one of the most dangerous infectious diseases plaguing the world. In the absence of any effective vaccines and with emerging drug resistance in the parasite against the majority of anti-malarial drugs, the search for new drugs is urgently needed for effective malaria treatment. The goal of the present study was to examine the compound library, based on indoles generated through diversity-oriented synthesis belonging to four different architecture, i.e., 1-aryltetrahydro/dihydro-β-carbolines and piperidine/pyrrolidine-fused indole derivatives, for their in vitro anti-plasmodial activity. Trifluoroacetic acid catalyzed transformation involving tryptamine and various aldehydes/ketones provided the library. Among all the compounds screened, 1-aryltetrahydro-β-carbolines 2 and 3 displayed significant anti-plasmodial activity against both the artemisinin-sensitive and artemisinin-resistant strain of Plasmodium falciparum. It was observed that these compounds inhibited the overall parasite growth in intra-erythrocytic developmental cycle (IDC) via reactive oxygen species-mediated parasitic death and thus could be potential anti-malarial compounds. Overall the compounds 2 and 3 identified in this study shows promising anti-plasmodial activity that can kill both artemisinin-sensitive and artemisinin-resistant strains of P. falciparum.read more
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A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria
Alassane Mbengue,Souvik Bhattacharjee,Trupti Pandharkar,Liu Liu,Guillermina Estiu,Robert V. Stahelin,Shahir S. Rizk,Dieudonné Lemuh Njimoh,Yana Ryan,Kesinee Chotivanich,Chea Nguon,Mehdi Ghorbal,Jose-Juan Lopez-Rubio,Michael E. Pfrender,Scott J. Emrich,Narla Mohandas,Arjen M. Dondorp,Olaf Wiest,Kasturi Haldar +18 more
Abstract: Artemisinins are the cornerstone of anti-malarial drugs. Emergence and spread of resistance to them raises risk of wiping out recent gains achieved in reducing worldwide malaria burden and threatens future malaria control and elimination on a global level. Genome-wide association studies (GWAS) have revealed parasite genetic loci associated with artemisinin resistance. However, there is no consensus on biochemical targets of artemisinin. Whether and how these targets interact with genes identified by GWAS, remains unknown. Here we provide biochemical and cellular evidence that artemisinins are potent inhibitors of Plasmodium falciparum phosphatidylinositol-3-kinase (PfPI3K), revealing an unexpected mechanism of action. In resistant clinical strains, increased PfPI3K was associated with the C580Y mutation in P. falciparum Kelch13 (PfKelch13), a primary marker of artemisinin resistance. Polyubiquitination of PfPI3K and its binding to PfKelch13 were reduced by the PfKelch13 mutation, which limited proteolysis of PfPI3K and thus increased levels of the kinase, as well as its lipid product phosphatidylinositol-3-phosphate (PI3P). We find PI3P levels to be predictive of artemisinin resistance in both clinical and engineered laboratory parasites as well as across non-isogenic strains. Elevated PI3P induced artemisinin resistance in absence of PfKelch13 mutations, but remained responsive to regulation by PfKelch13. Evidence is presented for PI3P-dependent signalling in which transgenic expression of an additional kinase confers resistance. Together these data present PI3P as the key mediator of artemisinin resistance and the sole PfPI3K as an important target for malaria elimination.
Journal ArticleDOI
An insight into the recent developments in anti-infective potential of indole and associated hybrids
TL;DR: In this paper , the authors present a review of indole containing natural sources, marketed drugs, clinical candidates, and their biological activities like antibacterial, antifungal, anti-TB, antiviral, antimalarial, and anti-leishmanial activities.
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Synthesis, spectral analysis, DFT calculations, biological potential and molecular docking studies of indole appended pyrazolo-triazine
S. M. Basavarajaiah,G.Y. Nagesh,M.A. Javeed,Rashmi Bhat,S P Nethravathi,Jeelan Basha,K. Ramakrishna Reddy,C. Nisarga,Pooja Srinivas +8 more
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Spirooxindole: A Versatile Biologically Active Heterocyclic Scaffold
TL;DR: In this article , the authors summarized the recent development of both natural and synthetic spirooxindole-containing compounds prepared from isatin or its derivatives reported in the last five years.
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Current development of β-carboline derived potential antimalarial scaffolds.
TL;DR: In this article , the authors comprehensively encapsulated the clinical and preclinical antimalarial scaffolds comprising β-carboline moiety in their structure and illustrated various classes of natural and semi-synthetic analogues of β-carbolines.
References
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TL;DR: Widespread use of these drugs could roll back malaria and Artemisinin-derivative combinations are particularly effective, since they act rapidly and are well tolerated and highly effective.
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Aung Pyae Phyo,Standwell Nkhoma,Kasia Stepniewska,Kasia Stepniewska,Elizabeth A. Ashley,Elizabeth A. Ashley,Shalini Nair,Rose McGready,Rose McGready,Carit Ler Moo,Salma Al-Saai,Arjen M. Dondorp,Arjen M. Dondorp,Khin Maung Lwin,Pratap Singhasivanon,Nicholas P. J. Day,Nicholas P. J. Day,Nicholas J. White,Nicholas J. White,Tim J. Anderson,François Nosten,François Nosten +21 more
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Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria
Jane Achan,Ambrose Talisuna,Annette Erhart,Adoke Yeka,James K Tibenderana,Frederick N. Baliraine,Philip J. Rosenthal,Umberto D'Alessandro +7 more
TL;DR: In pregnancy, quinine continues to play a critical role in the management of malaria, especially in the first trimester, and it will remain a mainstay of treatment until safer alternatives become available.
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