Diversity-oriented synthesis and activity evaluation of substituted bicyclic lactams as anti-malarial against Plasmodium falciparum.
Vijeta Sharma,Shalini Agarwal,Sanjay M. Madurkar,Gaurav Datta,Poonam Dangi,Ramu Dandugudumula,Subhabrata Sen,Shailja Singh +7 more
TLDR
This study unveils a DOS-mediated exploration of small molecules with novel structural motifs that culminates in identifying a potential lead molecule against malaria.Abstract:
Background: Malaria remains the world’s most important devastating parasitic disease. Of the five species of Plasmodium known to infect and cause human malaria, Plasmodium falciparum is the most virulent and responsible for majority of the deaths caused by this disease. Mainstream drug therapy targets the asexual blood stage of the malaria parasite, as the disease symptoms are mainly associated with this stage. The prevalence of malaria parasite strains resistance to existing anti-malarial drugs has made the control of malaria even more challenging and hence the development of a new class of drugs is inevitable. Methods: Screening against different drug resistant and sensitive strains of P. falciparum was performed for few bicyclic lactam-based motifs, exhibiting a broad spectrum of activity with low toxicity generated via a focussed library obtained from diversity oriented synthesis (DOS). The synthesis and screening was followed by an in vitro assessment of the possible cytotoxic effect of this class of compounds on malaria parasite. Results: The central scaffold a chiral bicyclic lactam (A) and (A’) which were synthesized from (R)-phenylalaninol, levulinic acid and 3-(2-nitrophenyl) levulinic acid respectively. The DOS library was generated from A and from A’, by either direct substitution with o-nitrobenzylbromide at the carbon α- to the amide functionality or by conversion to fused pyrroloquinolines. Upon screening this diverse library for their anti-malarial activity, a dinitro/diamine substituted bicyclic lactam was found to demonstrate exceptional activity of >85% inhibition at 50 μM concentration across different strains of P. falciparum with no toxicity against mammalian cells. Also, loss of mitochondrial membrane potential, mitochondrial functionality and apoptosis was observed in parasite treated with diamine-substituted bicyclic lactams. Conclusions: This study unveils a DOS-mediated exploration of small molecules with novel structural motifs that culminates in identifying a potential lead molecule against malaria. In vitro investigations further reveal their cytocidal effect on malaria parasite growth. It is not the first time that DOS has been used as a strategy to identify therapeutic leads against malaria, but this study establishes the direct implications of DOS in scouting novel motifs with anti-malarial activity.read more
Citations
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Plasmodium Merozoite TRAP Family Protein Is Essential for Vacuole Membrane Disruption and Gamete Egress from Erythrocytes.
Daniel Y. Bargieri,Daniel Y. Bargieri,Sabine Thiberge,Chwen L. Tay,Alison F. Carey,Alison F. Carey,Alice Rantz,Florian Hischen,Audrey Lorthiois,Ursula Straschil,Pallavi Singh,Shailja Singh,Tony Triglia,Takafumi Tsuboi,Alan F. Cowman,Alan F. Cowman,Chetan E. Chitnis,Pietro Alano,Jake Baum,Gabriele Pradel,Catherine Lavazec,Robert Ménard +21 more
TL;DR: Surface-associated TRAP (thrombospondin-related anonymous protein) family proteins are conserved across the phylum of apicomplexan parasites, indicating that motor-binding TRAP family members function not just in parasite motility and cell invasion but also in membrane disruption and cell egress.
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Enantiopure Indolizinoindolones with in vitro Activity against Blood- and Liver-Stage Malaria Parasites
Nuno A. L. Pereira,Ângelo Monteiro,Marta Machado,Jiri Gut,Elies Molins,M. Jesus Perry,Jorge Dourado,Rui Moreira,Philip J. Rosenthal,Miguel Prudêncio,Maria M. M. Santos +10 more
TL;DR: An (S)‐tryptophanol‐derived isoindolinone was identified as a promising starting scaffold to search for novel antimalarials, combining excellent activity against both stages of the parasite′s life cycle with low cytotoxicity and excellent metabolic and chemical stability in vitro.
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Natural Product Inspired Novel Indole based Chiral Scaffold Kills Human Malaria Parasites via Ionic Imbalance Mediated Cell Death.
Poonam Dangi,Ravi Jain,Rajanikanth Mamidala,Vijeta Sharma,Shalini Agarwal,Chandramohan Bathula,M. Thirumalachary,Subhabrata Sen,Shailja Singh,Shailja Singh +9 more
TL;DR: It is shown that ionic imbalance caused by scaffold 7 induces autophagy that leads to onset of apoptosis in the parasite evident by the loss of mitochondrial membrane potential (ΔΨm) and DNA degradation.
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Integrative natural medicine inspired graphene nanovehicle-benzoxazine derivatives as potent therapy for cancer.
Naveen Kumar,Nisha Yadav,Nagarjuna Amarnath,Vijeta Sharma,Swapnil Shukla,Akriti Srivastava,Peeyush Prasad,Anup Kumar,Swati Garg,Shailja Singh,Shailja Singh,Seema Sehrawat,Bimlesh Lochab +12 more
TL;DR: Interestingly, the benzoxazine derivatives of eugenol with GO nanoparticle exhibited enhanced therapeutic potential in cancer cells and significant role of these derivatives on parasite suggesting its multi-pharmacological capability.
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A review on biomass-derived levulinic acid for application in drug synthesis
TL;DR: Levulinic acid (LEV) has been identified as a key building block chemical produced entirely from biomass and its derivatives can be used to synthesize a variety of value-added chemicals, such as 2-but...
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