- Le, Thuy, Kundu, Abhijit, Ghoshal, Atanu, Nguyen, Nghi, Preston, Sarah, Jiao, Yaqing, Ruan, Banfeng, Xue, Lian, Huang, Fei, Keiser, Jennifer, Hofmann, Andreas, Chang, Bill, Garcia-Bustos, Jose, Wells, Timothy, Palmer, Michael, Jabbar, Abdul, Gasser, Robin, Baell, Jonathan
- Authors: Le, Thuy , Kundu, Abhijit , Ghoshal, Atanu , Nguyen, Nghi , Preston, Sarah , Jiao, Yaqing , Ruan, Banfeng , Xue, Lian , Huang, Fei , Keiser, Jennifer , Hofmann, Andreas , Chang, Bill , Garcia-Bustos, Jose , Wells, Timothy , Palmer, Michael , Jabbar, Abdul , Gasser, Robin , Baell, Jonathan
- Date: 2019
- Type: Text , Journal article
- Relation: Journal of Medicinal Chemistry Vol. 62, no. 2 (2019), p. 1036-1053
- Full Text: false
- Reviewed:
- Description: Recently, we have discovered that the registered pesticide, tolfenpyrad, unexpectedly and potently inhibits the development of the L4 larval stage of the parasitic nematode Haemonchus contortus with an IC50 value of 0.03 mu M while displaying good selectivity, with an IC50 of 37.9 mu M for cytotoxicity. As a promising molecular template for medicinal chemistry optimization, we undertook anthelmintic structure-activity relationships for this chemical. Modifications of the left-hand side (LHS), right-hand side (RHS), and middle section of the scaffold were explored to produce a set of 57 analogues. Analogues 25, 29, and 33 were shown to be the most potent compounds of the series, with IC50 values at a subnanomolar level of potency against the chemotherapeutically relevant fourth larval (L4) stage of H. contortus. Selected compounds from the series also showed promising activity against a panel of other different parasitic nematodes, such as hookworms and whipworms.
Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation
- Stanley, Christopher, Maghzal, Ghassan, Ayer, Anita, Talib, Jihan, Giltrap, Andrew, Shengule, Sudhir, Wolhuter, Kathryn, Wang, Yutang, Chadha, Preet, Suarna, Cacang, Prysyazhna, Oleksandra, Scotcher, Jenna, Dunn, Louise, Prado, Fernanda, Nguyen, Nghi, Odiba, Jephthah, Baell, Johathan, Stasch, Johannes-Peter, Yamamoto, Yorihiro, Di Mascio, Paolo, Eaton, Philip, Payne, Richard, Stocker, Roland
- Authors: Stanley, Christopher , Maghzal, Ghassan , Ayer, Anita , Talib, Jihan , Giltrap, Andrew , Shengule, Sudhir , Wolhuter, Kathryn , Wang, Yutang , Chadha, Preet , Suarna, Cacang , Prysyazhna, Oleksandra , Scotcher, Jenna , Dunn, Louise , Prado, Fernanda , Nguyen, Nghi , Odiba, Jephthah , Baell, Johathan , Stasch, Johannes-Peter , Yamamoto, Yorihiro , Di Mascio, Paolo , Eaton, Philip , Payne, Richard , Stocker, Roland
- Date: 2019
- Type: Text , Journal article , Letter
- Relation: Nature Vol. 566, no. 7745 (2019), p. 548-552
- Full Text:
- Reviewed:
- Description: Singlet molecular oxygen (O-1(2)) has well-established roles in photosynthetic plants, bacteria and fungi(1-3), but not in mammals. Chemically generated O-1(2) oxidizes the amino acid tryptophan to precursors of a key metabolite called N-formylkynurenine(4), whereas enzymatic oxidation of tryptophan to N-formylkynurenine is catalysed by a family of dioxygenases, including indoleamine 2,3-dioxygenase 1(5). Under inflammatory conditions, this haem-containing enzyme is expressed in arterial endothelial cells, where it contributes to the regulation of blood pressure(6). However, whether indoleamine 2,3-dioxygenase 1 forms O-1(2) and whether this contributes to blood pressure control have remained unknown. Here we show that arterial indoleamine 2,3-dioxygenase 1 regulates blood pressure via formation of O-1(2). We observed that in the presence of hydrogen peroxide, the enzyme generates O-1(2) and that this is associated with the stereoselective oxidation of L-tryptophan to a tricyclic hydroperoxide via a previously unrecognized oxidative activation of the dioxygenase activity. The tryptophan-derived hydroperoxide acts in vivo as a signalling molecule, inducing arterial relaxation and decreasing blood pressure; this activity is dependent on Cys42 of protein kinase G1 alpha. Our findings demonstrate a pathophysiological role for O-1(2) in mammals through formation of an amino acid-derived hydroperoxide that regulates vascular tone and blood pressure under inflammatory conditions.
- Authors: Stanley, Christopher , Maghzal, Ghassan , Ayer, Anita , Talib, Jihan , Giltrap, Andrew , Shengule, Sudhir , Wolhuter, Kathryn , Wang, Yutang , Chadha, Preet , Suarna, Cacang , Prysyazhna, Oleksandra , Scotcher, Jenna , Dunn, Louise , Prado, Fernanda , Nguyen, Nghi , Odiba, Jephthah , Baell, Johathan , Stasch, Johannes-Peter , Yamamoto, Yorihiro , Di Mascio, Paolo , Eaton, Philip , Payne, Richard , Stocker, Roland
- Date: 2019
- Type: Text , Journal article , Letter
- Relation: Nature Vol. 566, no. 7745 (2019), p. 548-552
- Full Text:
- Reviewed:
- Description: Singlet molecular oxygen (O-1(2)) has well-established roles in photosynthetic plants, bacteria and fungi(1-3), but not in mammals. Chemically generated O-1(2) oxidizes the amino acid tryptophan to precursors of a key metabolite called N-formylkynurenine(4), whereas enzymatic oxidation of tryptophan to N-formylkynurenine is catalysed by a family of dioxygenases, including indoleamine 2,3-dioxygenase 1(5). Under inflammatory conditions, this haem-containing enzyme is expressed in arterial endothelial cells, where it contributes to the regulation of blood pressure(6). However, whether indoleamine 2,3-dioxygenase 1 forms O-1(2) and whether this contributes to blood pressure control have remained unknown. Here we show that arterial indoleamine 2,3-dioxygenase 1 regulates blood pressure via formation of O-1(2). We observed that in the presence of hydrogen peroxide, the enzyme generates O-1(2) and that this is associated with the stereoselective oxidation of L-tryptophan to a tricyclic hydroperoxide via a previously unrecognized oxidative activation of the dioxygenase activity. The tryptophan-derived hydroperoxide acts in vivo as a signalling molecule, inducing arterial relaxation and decreasing blood pressure; this activity is dependent on Cys42 of protein kinase G1 alpha. Our findings demonstrate a pathophysiological role for O-1(2) in mammals through formation of an amino acid-derived hydroperoxide that regulates vascular tone and blood pressure under inflammatory conditions.
Novel 1-Methyl-1H-pyrazole-5-carboxamide derivatives with potent anthelmintic activity
- Le, Thuy, Kundu, Abhijit, Ghoshal, Atanu, Nguyen, Nghi, Preston, Sarah, Jiao, Yaqing, Ruan, Banfeng, Xue, Lian, Huang, Fei, Keiser, Jennifer, Hofmann, Andreas, Chang, Bill, Garcia-Bustos, Jose, Wells, Timothy, Palmer, Michael, Jabbar, Abdul, Gasser, Robin, Baell, Jonathan
- Authors: Le, Thuy , Kundu, Abhijit , Ghoshal, Atanu , Nguyen, Nghi , Preston, Sarah , Jiao, Yaqing , Ruan, Banfeng , Xue, Lian , Huang, Fei , Keiser, Jennifer , Hofmann, Andreas , Chang, Bill , Garcia-Bustos, Jose , Wells, Timothy , Palmer, Michael , Jabbar, Abdul , Gasser, Robin , Baell, Jonathan
- Date: 2019
- Type: Text , Journal article
- Relation: Journal of Medicinal Chemistry Vol. 62, no. 7 (2019), p. 3367-3380
- Full Text: false
- Reviewed:
- Description: A phenotypic screen of two different libraries of small molecules against the motility and development of the parasitic nematode Haemonchus contortus led to the identification of two 1-methyl-1H-pyrazole-5-carboxamide derivatives. Medicinal chemistry optimization targeted modifications of the left-hand side, middle section, and right-hand side of the hybrid structure of these two hits to elucidate the structure-activity relationship (SAR). Initial SAR around these hits allowed for the iterative and directed assembly of a focused set of 30 analogues of their hybrid structure. Compounds 10, 17, 20, and 22 were identified as the most potent compounds, inhibiting the development of the fourth larval (L4) stage of H. contortus at sub-nanomolar potencies while displaying strong selectivity toward the parasite when tested in vitro against the human MCF10A cell line. In addition, compounds 9 and 27 showed promising activity against a panel of other parasitic nematodes, including hookworms and whipworms.
Advances in the discovery and development of anthelmintics by harnessing natural product scaffolds
- Herath, H. M. P. Dilrukshi, Taki, Aya, Sleebs, Brad, Hofmann, Andreas, Nguyen, Nghi, Preston, Sarah, Davis, Rohan, Jabbar, Abdul, Gasser, Robin
- Authors: Herath, H. M. P. Dilrukshi , Taki, Aya , Sleebs, Brad , Hofmann, Andreas , Nguyen, Nghi , Preston, Sarah , Davis, Rohan , Jabbar, Abdul , Gasser, Robin
- Date: 2021
- Type: Text , Book chapter
- Relation: Advances in Parasitology p. 203-251
- Full Text: false
- Reviewed:
- Description: Widespread resistance to currently-used anthelmintics represents a major obstacle to controlling parasitic nematodes of livestock animals. Given the reliance on anthelmintics in many control regimens, there is a need for the continued discovery and development of new nematocides. Enabling such a focus are: (i) the major chemical diversity of natural products; (ii) the availability of curated, drug-like extract-, fraction- and/or compound-libraries from natural sources; (iii) the utility and practicality of well-established whole-worm bioassays for Haemonchus contortus—an important parasitic nematodes of livestock—to screen natural product libraries; and (iv) the availability of advanced chromatographic (HPLC), spectroscopic (NMR) and spectrometric (MS) techniques for bioassay-guided fractionation and structural elucidation. This context provides a sound basis for the identification and characterisation of anthelmintic candidates from natural sources. This chapter provides a background on the importance and impact of helminth infections/diseases, parasite control and aspects of drug discovery, and reviews recent work focused on (i) screening well-defined compound libraries to establish the methods needed for large-scale screening of natural extract libraries; (ii) discovering plant and marine extracts with nematocidal or nematostatic activity, and purifying bioactive compounds and assessing their potential for further development; and (iii) synthesising analogues of selected purified natural compounds for the identification of possible ‘lead’ candidates. The chapter describes some lessons learned from this work and proposes future areas of focus for drug discovery. Collectively, the findings from this recent work show potential for selected natural product scaffolds as candidates for future development. Developing such candidates via future chemical optimisation, efficacy and safety evaluations, broad spectrum activity assessments, and target identification represents an exciting prospect and, if successful, could pave the way to subsequent pre-clinical and clinical evaluations. © 2021 Elsevier Ltd
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