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Uday Bandyopadhyay - One of the best experts on this subject based on the ideXlab platform.

  • Hydrazonophenol, a Food Vacuole-Targeted and Ferriprotoporphyrin IX-Interacting Chemotype Prevents Drug-Resistant Malaria
    2018
    Co-Authors: Shubhra Jyoti Saha, Asim Azhar Siddiqui, Saikat Pramanik, Debanjan Saha, Somnath Mazumder, Subhashis Debsharma, Shiladitya Nag, Chinmoy Banerjee, Uday Bandyopadhyay
    Abstract:

    The rapid emergence of resistance against frontline Antimalarial drugs essentially warrants the identification of new-generation Antimalarials. Here, we describe the synthesis of (E)-2-isopropyl-5-methyl-4-((2-(pyridin-4-yl)­hydrazono)­methyl)­phenol (18), which binds ferriprotoporphyrin-IX (FeIII-PPIX) (Kd = 33 nM) and offers Antimalarial activity against chloroquine-resistant and sensitive strains of Plasmodium falciparum in vitro. Structure–function analysis reveals that compound 18 binds FeIII-PPIX through the −CN–NH– moiety and 2-pyridyl substitution at the hydrazine counterpart plays a critical role in Antimalarial efficacy. Live cell confocal imaging using a fluorophore-tagged compound confirms its accumulation inside the acidic food vacuole (FV) of P. falciparum. Furthermore, this compound concentration-dependently elevates the pH in FV, implicating a plausible interference with FeIII-PPIX crystallization (hemozoin formation) by a dual function: increasing the pH and binding free FeIII-PPIX. Different off-target bioassays reduce the possibility of the promiscuous nature of compound 18. Compound 18 also exhibits potent in vivo Antimalarial activity against chloroquine-resistant P. yoelii and P. berghei ANKA (causing cerebral malaria) in mice with negligible toxicity

  • Antimalarial drugs inhibiting hemozoin β hematin formation a mechanistic update
    Life Sciences, 2007
    Co-Authors: Sanjay Kumar, Mithu Guha, Vinay Choubey, Pallab Maity, Uday Bandyopadhyay
    Abstract:

    Digestion of hemoglobin in the food vacuole of the malaria parasite produces very high quantities of redox active toxic free heme. Hemozoin (β-hematin) formation is a unique process adopted by Plasmodium sp. to detoxify free heme. Hemozoin formation is a validated target for most of the well-known existing Antimalarial drugs and considered to be a suitable target to develop new Antimalarials. Here we discuss the possible mechanisms of free heme detoxification in the malaria parasite and the mechanistic details of compounds, which offer Antimalarial activity by inhibiting hemozoin formation. The chemical nature of new Antimalarial compounds showing Antimalarial activity through the inhibition of hemozoin formation has also been incorporated, which may help to design future Antimalarials with therapeutic potential against multi-drug resistant malaria.

  • Antimalarial drugs inhibiting hemozoin (β-hematin) formation: A mechanistic update
    Life sciences, 2006
    Co-Authors: Sanjay Kumar, Mithu Guha, Vinay Choubey, Pallab Maity, Uday Bandyopadhyay
    Abstract:

    Digestion of hemoglobin in the food vacuole of the malaria parasite produces very high quantities of redox active toxic free heme. Hemozoin (beta-hematin) formation is a unique process adopted by Plasmodium sp. to detoxify free heme. Hemozoin formation is a validated target for most of the well-known existing Antimalarial drugs and considered to be a suitable target to develop new Antimalarials. Here we discuss the possible mechanisms of free heme detoxification in the malaria parasite and the mechanistic details of compounds, which offer Antimalarial activity by inhibiting hemozoin formation. The chemical nature of new Antimalarial compounds showing Antimalarial activity through the inhibition of hemozoin formation has also been incorporated, which may help to design future Antimalarials with therapeutic potential against multi-drug resistant malaria.

Feng Zhao - One of the best experts on this subject based on the ideXlab platform.

  • Quinoline hybrids and their antiplasmodial and Antimalarial activities.
    European journal of medicinal chemistry, 2017
    Co-Authors: Chuan Gao, Shu Zhang, Lian-shun Feng, Feng Zhao
    Abstract:

    Abstract Malaria, in particular infection with P. falciparum (the most lethal of the human malaria parasite species, responsible for nearly one million deaths every year), is one of the most devastating and common infectious disease throughout the world. Beginning with quinine, quinoline containing compounds have long been used in clinical treatment of malaria and remained the mainstays of chemotherapy against malaria. The emergence of P. falciparum strains resistant to almost all Antimalarials prompted medicinal chemists and biologists to study their effective replacement with an alternative mechanism of action and new molecules. Combination with variety of quinolines and other active moieties may increase the antiplasmodial and Antimalarial activities and reduce the side effects. Thus, hybridization is a very attractive strategy to develop novel Antimalarials. This review aims to summarize the recent advances towards the discovery of antiplasmodial and Antimalarial hybrids including quinoline skeleton to provide an insight for rational designs of more active and less toxic quinoline hybrids Antimalarials.

Bernard J. Brabin - One of the best experts on this subject based on the ideXlab platform.

  • Antimalarial Drugs in Pregnancy: A Review
    Current drug safety, 2006
    Co-Authors: François Nosten, Rose Mcgready, Umberto D'alessandro, Ana Bonell, Francine H. Verhoeff, Clara Menéndez, Thenonest Mutabingwa, Bernard J. Brabin
    Abstract:

    In this review we examine the available information on the safety of Antimalarials in pregnancy, from both animal and human studies. The Antimalarials that can be used in pregnancy include (1) chloroquine, (2) amodiaquine, (3) quinine, (4) azithromycin, (5) sulfadoxine-pyrimethamine, (6) mefloquine, (7) dapsone-chlorproguanil, (8) artemisinin derivatives, (9) atovaquone-proguanil and (10) lumefantrine. Antimalarial drugs that should not be used in pregnancy including (1) halofantrine, (2) tetracycline/doxycycline, and (3) primaquine. There are few studies in humans on the pharmacokinetics, safety and efficacy of Antimalarials in pregnancy. This is because pregnant women are systematically excluded from clinical trials. The absence of adequate safety data, especially in the first trimester, is an important obstacle to developing treatment strategies. The pharmacokinetics of most Antimalarial drugs are also modified in pregnancy and dosages will need to be adapted. Other factors, including HIV status, drug interactions with antiretrovirals, the influence of haematinics and host genetic polymorphisms may influence safety and efficacy. For these reasons there is an urgent need to assess the safety and efficacy of Antimalarial treatments in pregnancy, including artemisinin based combination therapies.

Sandra Gemma - One of the best experts on this subject based on the ideXlab platform.

  • combining 4 aminoquinoline and clotrimazole based pharmacophores toward innovative and potent hybrid Antimalarials
    Journal of Medicinal Chemistry, 2009
    Co-Authors: Sandra Gemma, Giuseppe Campiani, Bhupendra P Joshi, Gagan Kukreja, Salvatore Sanna Coccone, Matteo Bernetti, Vito Nacci, Stefania Butini, M. Persico, Isabella Fiorini
    Abstract:

    Antimalarial agents structurally based on novel pharmacophores, synthesized by low-cost synthetic procedures and characterized by low potential for developing resistance are urgently needed. Recently, we developed an innovative class of Antimalarials based on a polyaromatic pharmacophore. Hybridizing the 4-aminoquinoline or the 9-aminoacridine system of known Antimalarials with the clotrimazole-like pharmacophore, characterized by a polyarylmethyl group, we describe herein the development of a unique class (4a-l and 5a-c) of Antimalarials selectively interacting with free heme and interfering with Plasmodium falciparum (Pf) heme metabolism. Combination of the polyarylmethyl system, able to form and stabilize radical intermediates, with the iron-complexing and conjugation-mediated electron transfer properties of the 4(9)-aminoquinoline-(acridine) system led to potent Antimalarials in vitro against chloroquine sensitive and resistant Pf strains. Among the compounds synthesized, 4g was active in vivo against P. chabaudi and P. berghei after oral administration and, possessing promising pharmacokinetic properties, it is a candidate for further preclinical development.

  • design and synthesis of potent Antimalarial agents based on clotrimazole scaffold exploring an innovative pharmacophore
    Journal of Medicinal Chemistry, 2007
    Co-Authors: Sandra Gemma, Giuseppe Campiani, Bhupendra P Joshi, Gagan Kukreja, Stefania Butini, M. Persico, Bruno Catalanotti, Ettore Novellino, Ernesto Fattorusso, Vito Nacci
    Abstract:

    Identification of new molecular scaffolds structurally unrelated to known Antimalarials may represent a valid strategy to overcome resistance of P. falciparum (Pf) to currently available drugs. We describe herein the investigation of a new polycyclic pharmacophore, related to clotrimazole, to develop innovative Antimalarial agents. This study allowed us to discover compounds characterized by a high in vitro potency, particularly against Pf CQ-resistant strains selectively targeting free heme, which are easy to synthesize by low-cost synthetic strategies.

Dawn Wood - One of the best experts on this subject based on the ideXlab platform.

  • The Safety of Antimalarial Drugs in Pregnancy
    Drug Safety, 1996
    Co-Authors: Penelope A. Phillips-howard, Dawn Wood
    Abstract:

    Alternative drugs to chloroquine are required to prevent the deleterious effects of malaria in pregnancy. Fear of potential toxicity has limited Antimalarial drug use in pregnancy. Animal toxicity studies have documented teratogenicity when Antimalarials are administered at high dosages. Excepting the tetracyclines, there is no evidence to suggest that, at standard dosages, any of the Antimalarial drugs are teratogenic. Primaquine is not recommended because of the potential risk of haemolytic effects in the fetus. Rates of spontaneous abortion and birth defects were comparable in pregnant women taking mefloquine, compared with chloroquine-proguanil, or pyrimethamine-sulfadoxine prophylaxis, in the first trimester of pregnancy. Standard doses of quinine do not increase the risk of abortion or preterm delivery. Therapeutic mefloquine does not provoke hypoglycaemia. There is no evidence in the literature to support the hypothetical risk of kernicterus in the newborn, following exposure to Antimalarial drugs containing sulphonamides or sulphones prior to delivery. Documentation of the safety of doxycycline, halofantrine, and the artemisinin derivatives in the treatment of malaria in pregnant women is currently limited.