Design, synthesis, and application of novel triclosan prodrugs as potential antimalarial and antibacterial agents

Karmodiya, Krishanpal; Parasuraman, Prasanna; Surolia, Avadhesha; Surolia, Namita

doi:10.1016/j.bmc.2008.04.006

Cited by 19 publications

(18 citation statements)

References 32 publications

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“…Average-sum FIC 50 was determined by the sum of the ratio of the IC 50 of each drug in combination treatments over the IC 50 of each of the drug administered alone. Synergistic activity was defined by a sum FIC ratio of Յ0.5 according to previously published definitions (4,13,21).…”

Section: Methodsmentioning

confidence: 99%

Harmine Is a Potent Antimalarial Targeting Hsp90 and Synergizes with Chloroquine and Artemisinin

Shahinas

MacMullin

Benedict

et al. 2012

Antimicrob Agents Chemother

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Previous studies have shown an antimalarial effect of total alkaloids extracted from leaves of Guiera senegalensis from Mali in West Africa. We independently observed that the beta-carboline alkaloid harmine obtained from a natural product library screen inhibited Plasmodium falciparum heat shock protein 90 (PfHsp90) ATP-binding domain. In this study, we confirmed harmine-PfHsp90-specific affinity using surface plasmon resonance analysis (dissociation constant [K d ] of 40 M). In contrast, the related compound harmalol bound human Hsp90 (HsHsp90) (K d of 224 M) more tightly than PfHsp90 (K d of 7,010 M). Site-directed mutagenesis revealed that Arg98 in PfHsp90 is essential for harmine selectivity. In keeping with our model indicating that Hsp90 inhibition affords synergistic combinations with existing antimalarials, we demonstrated that harmine potentiates the effect of chloroquine and artemisinin in vitro and in the Plasmodium berghei mouse model. These findings have implications for the development of novel therapeutic combinations that are synergistic with existing antimalarials.

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Section: Methodsmentioning

confidence: 99%

Harmine Is a Potent Antimalarial Targeting Hsp90 and Synergizes with Chloroquine and Artemisinin

Shahinas

MacMullin

Benedict

et al. 2012

Antimicrob Agents Chemother

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“…In continuation of earlier work by several groups of investigators, this study further explores the B-ring of triclosan, focusing specifically on its 2 0 -position and the intricate molecular interactions using docking analysis (6,7,15,19). The chloro group at 2 0 -position of triclosan is shown to have close proximity to Ala 217 and pyrophosphate moiety of NAD 1 .…”

Section: Introductionmentioning

confidence: 88%

“…In type II FAS each reaction of fatty acid synthesis is catalyzed by a physically distinct enzyme in contrast to a single multifunctional enzyme in type I FAS that catalyzes all the required reactions (5). Because of these differences in the organization of the type I and type II FAS, the latter is considered to be suitable as a target for developing antimicrobial and antiparasitic agents as well as vaccines against the organisms (6,7).…”

Section: Introductionmentioning

confidence: 99%

Design, development, synthesis, and docking analysis of 2′‐substituted triclosan analogs as inhibitors for Plasmodium falciparum Enoyl‐ACP reductase

et al. 2009

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SummaryA structure-based approach has been adopted to develop 2 0 -substituted analogs of triclosan. The Cl at position 2 0 in ring B of triclosan was chemically substituted with other functional groups like NH 2 , NO 2 and their inhibitory potencies against PfENR were determined. The binding energies of the 2 0 substituted analogs of triclosan for enoyl-acyl carrier protein reductase (ENR) of Plasmodium falciparum were determined using Autodock. Based on the autodock results, we synthesized the potential compounds. The IC 50 and inhibition constant (K i ) of 2 0 substituted analogs of triclosan were determined against purified PfENR. Among them, two compounds, 2-(2 0 -Amino-4 0 -chloro-phenoxy)-5-chloro-phenol (compound 4) and 5-chloro-2-(4 0 -chloro-2 0 -nitro-phenoxy)-phenol) (compound 5) exhibited good potencies. Compound 4 followed uncompetitive inhibition kinetics with crotonoyl CoA and competitive with NADH. It was shown to have an IC 50 of 110 nM; inhibition constant was 104 nM with the substrate and 61 nM with the cofactor. IC 50 of compound 5 was determined to be 229 nM. Compounds 4 and 5 showed significant inhibition of the parasite growth in P. falciparum culture.

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“…1. In this context, several triclosan analogs were designed by our group (23)(24)(25) and we have also discovered that rhodanines are potent inhibitors of PfENR (26). Triclosan is also shown to be potent against Plasmodium berghei in vivo mice infections (3) and in vitro human cells (27).…”

Section: Introductionmentioning

confidence: 99%

X‐ray crystallographic analysis of the complexes of enoyl acyl carrier protein reductase of Plasmodium falciparum with triclosan variants to elucidate the importance of different functional groups in enzyme inhibition

Maity¹,

Bhargav²,

Sankaran³

et al. 2010

IUBMB Life

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SummaryTriclosan, a well-known inhibitor of Enoyl Acyl Carrier Protein Reductase (ENR) from several pathogenic organisms, is a promising lead compound to design effective drugs. We have solved the X-ray crystal structures of Plasmodium falciparum ENR in complex with triclosan variants having different substituted and unsubstituted groups at different key functional locations. The structures revealed that 4 and 2 0 substituted compounds have more interactions with the protein, cofactor, and solvents when compared with triclosan. New water molecules were found to interact with some of these inhibitors. Substitution at the 2 0 position of triclosan caused the relocation of a conserved water molecule, leading to an additional hydrogen bond with the inhibitor. This observation can help in conserved water-based inhibitor design. 2 0 and 4 0 unsubstituted compounds showed a movement away from the hydrophobic pocket to compensate for the interactions made by the halogen groups of triclosan. This compound also makes additional interactions with the protein and cofactor which compensate for the lost interactions due to the unsubstitution at 2 0 and 4 0 . In cell culture, this inhibitor shows less potency, which indicates that the chlorines at 2 0 and 4 0 positions increase the ability of the inhibitor to cross multilayered membranes. This knowledge helps us to modify the different functional groups of triclosan to get more potent inhibitors. IUBMBIUBMB Life, 62(6): [467][468][469][470][471][472][473][474][475][476] 2010

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Design, synthesis, and application of novel triclosan prodrugs as potential antimalarial and antibacterial agents

Cited by 19 publications

References 32 publications

Harmine Is a Potent Antimalarial Targeting Hsp90 and Synergizes with Chloroquine and Artemisinin

Harmine Is a Potent Antimalarial Targeting Hsp90 and Synergizes with Chloroquine and Artemisinin

Design, development, synthesis, and docking analysis of 2′‐substituted triclosan analogs as inhibitors for Plasmodium falciparum Enoyl‐ACP reductase

X‐ray crystallographic analysis of the complexes of enoyl acyl carrier protein reductase of Plasmodium falciparum with triclosan variants to elucidate the importance of different functional groups in enzyme inhibition

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