Anti-schistosomal activities of quinoxaline-containing compounds: From hit identification to lead optimisation

Padalino, Gilda; Padalino, Gilda; El-Sakkary, Nelly; Liu, Lawrence J.; Liu, Chenxi; Harte, Danielle; Barnes, Rachel; Sayers, Edward; Forde-Thomas, Josephine; Whiteland, Helen; Bassetto, Marcella; Ferla, Salvatore; Johnson, George; Jones, Arwyn T.; Caffrey, Conor R.; Chalmers, Iain; Brancale, Andrea; Hoffmann, Karl F.

doi:10.1016/j.ejmech.2021.113823

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Anti-schistosomal activities of quinoxaline-containing compounds: From hit identification to lead optimisation

Gilda Padalino

, Gilda Padalino, Nelly El-Sakkary, Lawrence J. Liu, Chenxi Liu, Danielle Harte, Rachel Barnes, Edward Sayers, Josephine Forde-Thomas, Helen Whiteland, Marcella Bassetto, Salvatore Ferla

, George Johnson

, Arwyn T. Jones, Conor R. Caffrey, Iain Chalmers, Andrea Brancale, Karl F. Hoffmann

European Journal of Medicinal Chemistry, Volume: 226, Start page: 113823

Swansea University Authors: Gilda Padalino , Danielle Harte, Rachel Barnes, Marcella Bassetto, Salvatore Ferla , George Johnson

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DOI (Published version): 10.1016/j.ejmech.2021.113823

Abstract

Schistosomiasis is a neglected disease of poverty that is caused by infection with blood fluke species contained within the genus Schistosoma. For the last 40 years, control of schistosomiasis in endemic regions has predominantly been facilitated by administration of a single drug, praziquantel. Due...

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Published in:	European Journal of Medicinal Chemistry
ISSN:	0223-5234
Published:	Elsevier BV 2021
Online Access:	Check full text
URI:	https://cronfa.swan.ac.uk/Record/cronfa57836

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For the last 40 years, control of schistosomiasis in endemic regions has predominantly been facilitated by administration of a single drug, praziquantel. Due to limitations in this mono-chemotherapeutic approach for sustaining schistosomiasis control into the future, alternative anti-schistosomal compounds are increasingly being sought by the drug discovery community. Herein, we describe a multi-pronged, integrated strategy that led to the identification and further exploration of the quinoxaline core as a promising anti-schistosomal scaffold.Firstly, phenotypic screening of commercially available small molecules resulted in the identification of a moderately active hit compound against Schistosoma mansoni (1, EC50 = 4.59 μM on schistosomula). Secondary exploration of the chemical space around compound 1 led to the identification of a quinoxaline-core containing, non-genotoxic lead (compound 22). Compound 22 demonstrated substantially improved activities on both intra-mammalian (EC50 = 0.44 μM, 0.20 μM and 84.7 nM, on schistosomula, juvenile and adult worms, respectively) and intra-molluscan (sporocyst) S. mansoni lifecycle stages. Further medicinal chemistry optimisation of compound 22, resulting in the generation of 20 additional analogues, improved our understanding of the structure-activity relationship and resulted in considerable improvements in both anti-schistosome potency and selectivity (e.g. compound 30; EC50 = 2.59 nM on adult worms; selectivity index compared to the HepG2 cell line = 348). Some derivatives of compound 22 (e.g. 31 and 33) also demonstrated significant activity against the two other medically important species, Schistosoma haematobium and Schistosoma japonicum. Further optimisation of this class of anti-schistosomal is ongoing and could lead to the development of an urgently needed alternative to praziquantel for assisting in schistosomiasis elimination strategies.</abstract><type>Journal Article</type><journal>European Journal of Medicinal Chemistry</journal><volume>226</volume><journalNumber/><paginationStart>113823</paginationStart><paginationEnd/><publisher>Elsevier BV</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>0223-5234</issnPrint><issnElectronic/><keywords>Schistosomiasis, Quinoxaline, SAR, Drug discovery</keywords><publishedDay>15</publishedDay><publishedMonth>12</publishedMonth><publishedYear>2021</publishedYear><publishedDate>2021-12-15</publishedDate><doi>10.1016/j.ejmech.2021.113823</doi><url/><notes/><college>COLLEGE NANME</college><department>Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDS</DepartmentCode><institution>Swansea University</institution><apcterm>Another institution paid the OA fee</apcterm><funders>Welsh Government, Life SciencesResearch Network Wales scheme and the Wellcome Trust (107475/Z/15/Z)</funders><projectreference/><lastEdited>2022-10-27T16:05:54.3130940</lastEdited><Created>2021-09-10T14:17:25.2859581</Created><path><level id="1">Faculty of Science and Engineering</level><level id="2">School of Engineering and Applied Sciences - Chemistry</level></path><authors><author><firstname>Gilda</firstname><surname>Padalino</surname><orcid>0000-0001-8580-1293</orcid><order>1</order></author><author><firstname>Gilda</firstname><surname>Padalino</surname><order>2</order></author><author><firstname>Nelly</firstname><surname>El-Sakkary</surname><order>3</order></author><author><firstname>Lawrence J.</firstname><surname>Liu</surname><order>4</order></author><author><firstname>Chenxi</firstname><surname>Liu</surname><order>5</order></author><author><firstname>Danielle</firstname><surname>Harte</surname><order>6</order></author><author><firstname>Rachel</firstname><surname>Barnes</surname><order>7</order></author><author><firstname>Edward</firstname><surname>Sayers</surname><order>8</order></author><author><firstname>Josephine</firstname><surname>Forde-Thomas</surname><order>9</order></author><author><firstname>Helen</firstname><surname>Whiteland</surname><order>10</order></author><author><firstname>Marcella</firstname><surname>Bassetto</surname><order>11</order></author><author><firstname>Salvatore</firstname><surname>Ferla</surname><orcid>0000-0002-5918-9237</orcid><order>12</order></author><author><firstname>George</firstname><surname>Johnson</surname><orcid>0000-0001-5643-9942</orcid><order>13</order></author><author><firstname>Arwyn T.</firstname><surname>Jones</surname><order>14</order></author><author><firstname>Conor R.</firstname><surname>Caffrey</surname><order>15</order></author><author><firstname>Iain</firstname><surname>Chalmers</surname><order>16</order></author><author><firstname>Andrea</firstname><surname>Brancale</surname><order>17</order></author><author><firstname>Karl F.</firstname><surname>Hoffmann</surname><order>18</order></author></authors><documents><document><filename>57836__20936__5f2e2a0e9cf94f9e966e89bd7f9fab9f.pdf</filename><originalFilename>57836.pdf</originalFilename><uploaded>2021-09-20T12:04:09.9245497</uploaded><type>Output</type><contentLength>1902945</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>© 2021 The Author(s). 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spelling	2022-10-27T16:05:54.3130940 v2 57836 2021-09-10 Anti-schistosomal activities of quinoxaline-containing compounds: From hit identification to lead optimisation 7e5526209f02734f57ba19b0d17604ec 0000-0001-8580-1293 Gilda Padalino Gilda Padalino true false 183eddc613937f235a28c10f63079678 Danielle Harte Danielle Harte true false ee057ea66de3c09af573e2dcf939f9ac Rachel Barnes Rachel Barnes true false b97beeed16f8e0524551233ade909565 Marcella Bassetto Marcella Bassetto true false d4c62248f510e3b221916989a7bbe6a6 0000-0002-5918-9237 Salvatore Ferla Salvatore Ferla true false 37d0f121db69fd09f364df89e4405e31 0000-0001-5643-9942 George Johnson George Johnson true false 2021-09-10 MEDS Schistosomiasis is a neglected disease of poverty that is caused by infection with blood fluke species contained within the genus Schistosoma. For the last 40 years, control of schistosomiasis in endemic regions has predominantly been facilitated by administration of a single drug, praziquantel. Due to limitations in this mono-chemotherapeutic approach for sustaining schistosomiasis control into the future, alternative anti-schistosomal compounds are increasingly being sought by the drug discovery community. Herein, we describe a multi-pronged, integrated strategy that led to the identification and further exploration of the quinoxaline core as a promising anti-schistosomal scaffold.Firstly, phenotypic screening of commercially available small molecules resulted in the identification of a moderately active hit compound against Schistosoma mansoni (1, EC50 = 4.59 μM on schistosomula). Secondary exploration of the chemical space around compound 1 led to the identification of a quinoxaline-core containing, non-genotoxic lead (compound 22). Compound 22 demonstrated substantially improved activities on both intra-mammalian (EC50 = 0.44 μM, 0.20 μM and 84.7 nM, on schistosomula, juvenile and adult worms, respectively) and intra-molluscan (sporocyst) S. mansoni lifecycle stages. Further medicinal chemistry optimisation of compound 22, resulting in the generation of 20 additional analogues, improved our understanding of the structure-activity relationship and resulted in considerable improvements in both anti-schistosome potency and selectivity (e.g. compound 30; EC50 = 2.59 nM on adult worms; selectivity index compared to the HepG2 cell line = 348). Some derivatives of compound 22 (e.g. 31 and 33) also demonstrated significant activity against the two other medically important species, Schistosoma haematobium and Schistosoma japonicum. Further optimisation of this class of anti-schistosomal is ongoing and could lead to the development of an urgently needed alternative to praziquantel for assisting in schistosomiasis elimination strategies. Journal Article European Journal of Medicinal Chemistry 226 113823 Elsevier BV 0223-5234 Schistosomiasis, Quinoxaline, SAR, Drug discovery 15 12 2021 2021-12-15 10.1016/j.ejmech.2021.113823 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee Welsh Government, Life SciencesResearch Network Wales scheme and the Wellcome Trust (107475/Z/15/Z) 2022-10-27T16:05:54.3130940 2021-09-10T14:17:25.2859581 Faculty of Science and Engineering School of Engineering and Applied Sciences - Chemistry Gilda Padalino 0000-0001-8580-1293 1 Gilda Padalino 2 Nelly El-Sakkary 3 Lawrence J. Liu 4 Chenxi Liu 5 Danielle Harte 6 Rachel Barnes 7 Edward Sayers 8 Josephine Forde-Thomas 9 Helen Whiteland 10 Marcella Bassetto 11 Salvatore Ferla 0000-0002-5918-9237 12 George Johnson 0000-0001-5643-9942 13 Arwyn T. Jones 14 Conor R. Caffrey 15 Iain Chalmers 16 Andrea Brancale 17 Karl F. Hoffmann 18 57836__20936__5f2e2a0e9cf94f9e966e89bd7f9fab9f.pdf 57836.pdf 2021-09-20T12:04:09.9245497 Output 1902945 application/pdf Version of Record true © 2021 The Author(s). This is an open access article under the CC BY license true eng https://creativecommons.org/licenses/by/4.0/
title	Anti-schistosomal activities of quinoxaline-containing compounds: From hit identification to lead optimisation
spellingShingle	Anti-schistosomal activities of quinoxaline-containing compounds: From hit identification to lead optimisation Gilda Padalino Danielle Harte Rachel Barnes Marcella Bassetto Salvatore Ferla George Johnson
title_short	Anti-schistosomal activities of quinoxaline-containing compounds: From hit identification to lead optimisation
title_full	Anti-schistosomal activities of quinoxaline-containing compounds: From hit identification to lead optimisation
title_fullStr	Anti-schistosomal activities of quinoxaline-containing compounds: From hit identification to lead optimisation
title_full_unstemmed	Anti-schistosomal activities of quinoxaline-containing compounds: From hit identification to lead optimisation
title_sort	Anti-schistosomal activities of quinoxaline-containing compounds: From hit identification to lead optimisation
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author_id_fullname_str_mv	7e5526209f02734f57ba19b0d17604ec_*_Gilda Padalino 183eddc613937f235a28c10f63079678__Danielle Harte ee057ea66de3c09af573e2dcf939f9ac__Rachel Barnes b97beeed16f8e0524551233ade909565__Marcella Bassetto d4c62248f510e3b221916989a7bbe6a6__Salvatore Ferla 37d0f121db69fd09f364df89e4405e31_*_George Johnson
author	Gilda Padalino Danielle Harte Rachel Barnes Marcella Bassetto Salvatore Ferla George Johnson
author2	Gilda Padalino Gilda Padalino Nelly El-Sakkary Lawrence J. Liu Chenxi Liu Danielle Harte Rachel Barnes Edward Sayers Josephine Forde-Thomas Helen Whiteland Marcella Bassetto Salvatore Ferla George Johnson Arwyn T. Jones Conor R. Caffrey Iain Chalmers Andrea Brancale Karl F. Hoffmann
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container_title	European Journal of Medicinal Chemistry
container_volume	226
container_start_page	113823
publishDate	2021
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issn	0223-5234
doi_str_mv	10.1016/j.ejmech.2021.113823
publisher	Elsevier BV
college_str	Faculty of Science and Engineering
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description	Schistosomiasis is a neglected disease of poverty that is caused by infection with blood fluke species contained within the genus Schistosoma. For the last 40 years, control of schistosomiasis in endemic regions has predominantly been facilitated by administration of a single drug, praziquantel. Due to limitations in this mono-chemotherapeutic approach for sustaining schistosomiasis control into the future, alternative anti-schistosomal compounds are increasingly being sought by the drug discovery community. Herein, we describe a multi-pronged, integrated strategy that led to the identification and further exploration of the quinoxaline core as a promising anti-schistosomal scaffold.Firstly, phenotypic screening of commercially available small molecules resulted in the identification of a moderately active hit compound against Schistosoma mansoni (1, EC50 = 4.59 μM on schistosomula). Secondary exploration of the chemical space around compound 1 led to the identification of a quinoxaline-core containing, non-genotoxic lead (compound 22). Compound 22 demonstrated substantially improved activities on both intra-mammalian (EC50 = 0.44 μM, 0.20 μM and 84.7 nM, on schistosomula, juvenile and adult worms, respectively) and intra-molluscan (sporocyst) S. mansoni lifecycle stages. Further medicinal chemistry optimisation of compound 22, resulting in the generation of 20 additional analogues, improved our understanding of the structure-activity relationship and resulted in considerable improvements in both anti-schistosome potency and selectivity (e.g. compound 30; EC50 = 2.59 nM on adult worms; selectivity index compared to the HepG2 cell line = 348). Some derivatives of compound 22 (e.g. 31 and 33) also demonstrated significant activity against the two other medically important species, Schistosoma haematobium and Schistosoma japonicum. Further optimisation of this class of anti-schistosomal is ongoing and could lead to the development of an urgently needed alternative to praziquantel for assisting in schistosomiasis elimination strategies.
published_date	2021-12-15T09:04:11Z
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score	11.058203

Anti-schistosomal activities of quinoxaline-containing compounds: From hit identification to lead optimisation

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