OpenLB
Open Library of Bioscience
Advanced Search
RSC medicinal chemistry
Feb 21, 2024;15 (2): 492-505.

Design, synthesis and evaluation of 2-phenylpyrimidine derivatives as novel antifungal agents targeting CYP51.

Zixuan Gao, Jiachen Zhang, Kejian Li, Yixiang Sun, Xudong Wu, Guoqi Zhang, Rongrong Liu, Rui Liu, Dongmei Zhao, Maosheng Cheng
Author Information
  1. Zixuan Gao: Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University 103 Wenhua Road, Shenhe District 110016 Shenyang China medchemzhao@163.com.
  2. Jiachen Zhang: Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University 103 Wenhua Road, Shenhe District 110016 Shenyang China medchemzhao@163.com.
  3. Kejian Li: Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University 103 Wenhua Road, Shenhe District 110016 Shenyang China medchemzhao@163.com.
  4. Yixiang Sun: Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University 103 Wenhua Road, Shenhe District 110016 Shenyang China medchemzhao@163.com.
  5. Xudong Wu: Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University 103 Wenhua Road, Shenhe District 110016 Shenyang China medchemzhao@163.com.
  6. Guoqi Zhang: Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University 103 Wenhua Road, Shenhe District 110016 Shenyang China medchemzhao@163.com.
  7. Rongrong Liu: Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University 103 Wenhua Road, Shenhe District 110016 Shenyang China medchemzhao@163.com.
  8. Rui Liu: Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University 103 Wenhua Road, Shenhe District 110016 Shenyang China medchemzhao@163.com.
  9. Dongmei Zhao: Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University 103 Wenhua Road, Shenhe District 110016 Shenyang China medchemzhao@163.com. ORCID
  10. Maosheng Cheng: Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University 103 Wenhua Road, Shenhe District 110016 Shenyang China medchemzhao@163.com.
PMID: 38389880 DOI: 10.1039/d3md00589e

Abstract

Invasive fungal infections, with high morbidity and mortality, have become one of the most serious threats to human health. There are a few kinds of clinical antifungal drugs but large amounts of them are used, so there is an urgent need for a new structural type of antifungal drug. In this study, we carried out three rounds of structural optimisation and modification of the compound YW-01, which was obtained from the preliminary screening of the group, by using the strategy of scaffold hopping. A series of novel phenylpyrimidine CYP51 inhibitors were designed and synthesised. antifungal testing showed that target compound C6 exhibited good efficacy against seven common clinically susceptible strains, which was significantly superior to the clinical first-line drug fluconazole. Subsequently tests on metabolic stability and cytotoxicity revealed that C6 was safe and stable for hepatic microsomal function. Finally, C6 warranted further exploration as a possible novel structural type of CYP51 inhibitor.

References

  1. J Med Chem. 2023 Jun 8;66(11):7497-7515 [PMID: 37218609]
  2. Int J Mol Sci. 2022 Mar 02;23(5): [PMID: 35269898]
  3. Drugs. 2011 Dec 24;71(18):2405-19 [PMID: 22141384]
  4. J Med Chem. 2003 Feb 13;46(4):474-85 [PMID: 12570370]
  5. Nat Rev Drug Discov. 2017 Sep;16(9):603-616 [PMID: 28496146]
  6. Curr Drug Targets. 2022;23(2):116-125 [PMID: 34551694]
  7. Eur J Med Chem. 2021 Dec 5;225:113740 [PMID: 34388384]
  8. J Med Chem. 2017 Mar 23;60(6):2193-2211 [PMID: 28051303]
  9. Antibiotics (Basel). 2020 Jul 25;9(8): [PMID: 32722455]
  10. Bioorg Med Chem. 2020 Apr 1;28(7):115398 [PMID: 32115335]
  11. Nat Microbiol. 2022 May;7(5):607-619 [PMID: 35508719]
  12. Biochem Pharmacol. 2017 Jun 1;133:86-96 [PMID: 27884742]
  13. Expert Rev Anti Infect Ther. 2017 Jun;15(6):577-584 [PMID: 28480775]
  14. J Biol Chem. 1984 Feb 10;259(3):1661-6 [PMID: 6420412]
  15. Eur J Med Chem. 2021 Nov 15;224:113715 [PMID: 34364163]
  16. Eur J Med Chem. 2019 Dec 1;183:111689 [PMID: 31541871]
  17. Microorganisms. 2022 Feb 10;10(2): [PMID: 35208864]
  18. J Med Chem. 2018 Jul 12;61(13):5484-5511 [PMID: 29294275]
  19. Eur J Med Chem. 2022 Apr 5;233:114195 [PMID: 35255313]
  20. Lancet Infect Dis. 2002 Sep;2(9):550-63 [PMID: 12206971]
  21. Molecules. 2010 Jun 09;15(6):4129-88 [PMID: 20657432]
  22. Expert Opin Pharmacother. 2010 Aug;11(12):2037-48 [PMID: 20536294]
  23. Front Microbiol. 2019 Feb 12;10:214 [PMID: 30809213]
  24. Science. 2012 May 11;336(6082):647 [PMID: 22582229]
  25. J Med Chem. 2023 Sep 28;66(18):13247-13265 [PMID: 37725043]
  26. RSC Med Chem. 2023 Jun 26;14(9):1603-1628 [PMID: 37731690]
  27. Infect Drug Resist. 2017 Aug 29;10:249-259 [PMID: 28919789]
  28. J Biol Chem. 2017 Apr 21;292(16):6728-6743 [PMID: 28258218]
Journal Article

Word Cloud

Created with Highcharts 10.0.0antifungalstructuralnovelCYP51C6clinicaltypedrugcompoundInvasivefungalinfectionshighmorbiditymortalitybecomeoneseriousthreatshumanhealthkindsdrugslargeamountsusedurgentneednewstudycarriedthreeroundsoptimisationmodificationYW-01obtainedpreliminaryscreeninggroupusingstrategyscaffoldhoppingseriesphenylpyrimidineinhibitorsdesignedsynthesisedtestingshowedtargetexhibitedgoodefficacysevencommonclinicallysusceptiblestrainssignificantlysuperiorfirst-linefluconazoleSubsequentlytestsmetabolicstabilitycytotoxicityrevealedsafestablehepaticmicrosomalfunctionFinallywarrantedexplorationpossibleinhibitorDesignsynthesisevaluation2-phenylpyrimidinederivativesagentstargeting

Similar Articles

Cited By

No available data.