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

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

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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
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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 &#x3BC;M 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 &#x3BC;M, 0.20 &#x3BC;M 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>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</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><order>1</order></author><author><firstname>Nelly</firstname><surname>El-Sakkary</surname><order>2</order></author><author><firstname>Lawrence J.</firstname><surname>Liu</surname><order>3</order></author><author><firstname>Chenxi</firstname><surname>Liu</surname><order>4</order></author><author><firstname>Danielle</firstname><surname>Harte</surname><order>5</order></author><author><firstname>Rachel</firstname><surname>Barnes</surname><order>6</order></author><author><firstname>Edward</firstname><surname>Sayers</surname><order>7</order></author><author><firstname>Josephine</firstname><surname>Forde-Thomas</surname><order>8</order></author><author><firstname>Helen</firstname><surname>Whiteland</surname><order>9</order></author><author><firstname>Marcella</firstname><surname>Bassetto</surname><orcid>0000-0002-2491-5868</orcid><order>10</order></author><author><firstname>Salvatore</firstname><surname>Ferla</surname><orcid>0000-0002-5918-9237</orcid><order>11</order></author><author><firstname>George</firstname><surname>Johnson</surname><orcid>0000-0001-5643-9942</orcid><order>12</order></author><author><firstname>Arwyn T.</firstname><surname>Jones</surname><order>13</order></author><author><firstname>Conor R.</firstname><surname>Caffrey</surname><order>14</order></author><author><firstname>Iain</firstname><surname>Chalmers</surname><order>15</order></author><author><firstname>Andrea</firstname><surname>Brancale</surname><order>16</order></author><author><firstname>Karl F.</firstname><surname>Hoffmann</surname><order>17</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>&#xA9; 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 183eddc613937f235a28c10f63079678 Danielle Harte Danielle Harte true false ee057ea66de3c09af573e2dcf939f9ac Rachel Barnes Rachel Barnes true false b97beeed16f8e0524551233ade909565 0000-0002-2491-5868 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 BMS 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 Biomedical Sciences COLLEGE CODE BMS 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 1 Nelly El-Sakkary 2 Lawrence J. Liu 3 Chenxi Liu 4 Danielle Harte 5 Rachel Barnes 6 Edward Sayers 7 Josephine Forde-Thomas 8 Helen Whiteland 9 Marcella Bassetto 0000-0002-2491-5868 10 Salvatore Ferla 0000-0002-5918-9237 11 George Johnson 0000-0001-5643-9942 12 Arwyn T. Jones 13 Conor R. Caffrey 14 Iain Chalmers 15 Andrea Brancale 16 Karl F. Hoffmann 17 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
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
author_id_str_mv 183eddc613937f235a28c10f63079678
ee057ea66de3c09af573e2dcf939f9ac
b97beeed16f8e0524551233ade909565
d4c62248f510e3b221916989a7bbe6a6
37d0f121db69fd09f364df89e4405e31
author_id_fullname_str_mv 183eddc613937f235a28c10f63079678_***_Danielle Harte
ee057ea66de3c09af573e2dcf939f9ac_***_Rachel Barnes
b97beeed16f8e0524551233ade909565_***_Marcella Bassetto
d4c62248f510e3b221916989a7bbe6a6_***_Salvatore Ferla
37d0f121db69fd09f364df89e4405e31_***_George Johnson
author Danielle Harte
Rachel Barnes
Marcella Bassetto
Salvatore Ferla
George Johnson
author2 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
format Journal article
container_title European Journal of Medicinal Chemistry
container_volume 226
container_start_page 113823
publishDate 2021
institution Swansea University
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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hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Engineering and Applied Sciences - Chemistry{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Engineering and Applied Sciences - Chemistry
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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 2021-12-15T04:06:30Z
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