Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against Mycobacterium abscessus and Mycobacterium avium, Two Emerging Human Pathogens

Matheus Andrade Meirelles; Vitor M. Almeida; Jaryd R. Sullivan; Ian de Toledo; Caio Vinicius dos Reis; Micael Rodrigues Cunha; Rachel Zigweid; Abraham Shim; Banumathi Sankaran; Elijah L. Woodward; Steve Seibold; Lijun Liu; Mohammad Rasel Mian; Kevin P. Battaile; Jennifer Riley; Christina Duncan; Frederick R.C. Simeons; Liam Ferguson; Halimatu Joji; Kevin D. Read; Scott Lovell; Bart L. Staker; Marcel A. Behr; Ronaldo A. Pilli; Rafael M. Couñago

doi:10.1021/acs.jmedchem.4c01594

Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against Mycobacterium abscessus and Mycobacterium avium, Two Emerging Human Pathogens

Matheus Andrade Meirelles, Vitor M. Almeida, Jaryd R. Sullivan, Ian de Toledo, Caio Vinicius dos Reis, Micael Rodrigues Cunha, Rachel Zigweid, Abraham Shim, Banumathi Sankaran, Elijah L. Woodward, Steve Seibold, Lijun Liu, Mohammad Rasel Mian, Kevin P. Battaile, Jennifer Riley, Christina Duncan, Frederick R.C. Simeons, Liam Ferguson, Halimatu Joji, Kevin D. ReadScott Lovell, Bart L. Staker, Marcel A. Behr, Ronaldo A. Pilli (Lead / Corresponding author), Rafael M. Couñago (Lead / Corresponding author)

Drug Discovery Unit

Research output: Contribution to journal › Article › peer-review

Abstract

Nontuberculous mycobacteria (NTM) are emerging human pathogens linked to severe pulmonary diseases. Current treatments involve the prolonged use of multiple drugs and are often ineffective. Bacterial dihydrofolate reductase (DHFR) is a key enzyme targeted by antibiotics in Gram-negative bacterial infections. However, existing DHFR inhibitors designed for Gram-negative bacteria often fail against mycobacterial DHFRs. Here, we detail the rational design of NTM DHFR inhibitors based on P218, a malarial DHFR inhibitor. We identified compound 8, a 2,4-diaminopyrimidine exhibiting improved pharmacological properties and activity against purified DHFR, and whole cell cultures of two predominant NTM species: Mycobacterium avium and Mycobacterium abscessus. This study underscores the potential of compound 8 as a promising candidate for the in vivo validation of DHFR as an effective treatment against NTM infections.

Original language	English
Pages (from-to)	19143-19164
Number of pages	22
Journal	Journal of Medicinal Chemistry
Volume	67
Issue number	21
Early online date	29 Oct 2024
DOIs	https://doi.org/10.1021/acs.jmedchem.4c01594
Publication status	Published - 14 Nov 2024

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

UN SDGs

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10.1021/acs.jmedchem.4c01594

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Andrade Meirelles, M., Almeida, V. M., Sullivan, J. R., de Toledo, I., dos Reis, C. V., Cunha, M. R., Zigweid, R., Shim, A., Sankaran, B., Woodward, E. L., Seibold, S., Liu, L., Mian, M. R., Battaile, K. P., Riley, J., Duncan, C., Simeons, F. R. C., Ferguson, L., Joji, H., ... Couñago, R. M. (2024). Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against Mycobacterium abscessus and Mycobacterium avium, Two Emerging Human Pathogens. Journal of Medicinal Chemistry, 67(21), 19143-19164. https://doi.org/10.1021/acs.jmedchem.4c01594

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title = "Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against Mycobacterium abscessus and Mycobacterium avium, Two Emerging Human Pathogens",

abstract = "Nontuberculous mycobacteria (NTM) are emerging human pathogens linked to severe pulmonary diseases. Current treatments involve the prolonged use of multiple drugs and are often ineffective. Bacterial dihydrofolate reductase (DHFR) is a key enzyme targeted by antibiotics in Gram-negative bacterial infections. However, existing DHFR inhibitors designed for Gram-negative bacteria often fail against mycobacterial DHFRs. Here, we detail the rational design of NTM DHFR inhibitors based on P218, a malarial DHFR inhibitor. We identified compound 8, a 2,4-diaminopyrimidine exhibiting improved pharmacological properties and activity against purified DHFR, and whole cell cultures of two predominant NTM species: Mycobacterium avium and Mycobacterium abscessus. This study underscores the potential of compound 8 as a promising candidate for the in vivo validation of DHFR as an effective treatment against NTM infections.",

author = "{Andrade Meirelles}, Matheus and Almeida, {Vitor M.} and Sullivan, {Jaryd R.} and {de Toledo}, Ian and {dos Reis}, {Caio Vinicius} and Cunha, {Micael Rodrigues} and Rachel Zigweid and Abraham Shim and Banumathi Sankaran and Woodward, {Elijah L.} and Steve Seibold and Lijun Liu and Mian, {Mohammad Rasel} and Battaile, {Kevin P.} and Jennifer Riley and Christina Duncan and Simeons, {Frederick R.C.} and Liam Ferguson and Halimatu Joji and Read, {Kevin D.} and Scott Lovell and Staker, {Bart L.} and Behr, {Marcel A.} and Pilli, {Ronaldo A.} and Cou{\~n}ago, {Rafael M.}",

note = "Publisher Copyright: {\textcopyright} 2024 American Chemical Society.",

year = "2024",

month = nov,

day = "14",

doi = "10.1021/acs.jmedchem.4c01594",

language = "English",

volume = "67",

pages = "19143--19164",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "21",

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Andrade Meirelles, M, Almeida, VM, Sullivan, JR, de Toledo, I, dos Reis, CV, Cunha, MR, Zigweid, R, Shim, A, Sankaran, B, Woodward, EL, Seibold, S, Liu, L, Mian, MR, Battaile, KP, Riley, J , Duncan, C , Simeons, FRC , Ferguson, L, Joji, H, Read, KD, Lovell, S, Staker, BL, Behr, MA, Pilli, RA & Couñago, RM 2024, 'Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against Mycobacterium abscessus and Mycobacterium avium, Two Emerging Human Pathogens', Journal of Medicinal Chemistry, vol. 67, no. 21, pp. 19143-19164. https://doi.org/10.1021/acs.jmedchem.4c01594

Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against Mycobacterium abscessus and Mycobacterium avium, Two Emerging Human Pathogens. / Andrade Meirelles, Matheus; Almeida, Vitor M.; Sullivan, Jaryd R. et al.
In: Journal of Medicinal Chemistry, Vol. 67, No. 21, 14.11.2024, p. 19143-19164.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against Mycobacterium abscessus and Mycobacterium avium, Two Emerging Human Pathogens

AU - Andrade Meirelles, Matheus

AU - Almeida, Vitor M.

AU - Sullivan, Jaryd R.

AU - de Toledo, Ian

AU - dos Reis, Caio Vinicius

AU - Cunha, Micael Rodrigues

AU - Zigweid, Rachel

AU - Shim, Abraham

AU - Sankaran, Banumathi

AU - Woodward, Elijah L.

AU - Seibold, Steve

AU - Liu, Lijun

AU - Mian, Mohammad Rasel

AU - Battaile, Kevin P.

AU - Riley, Jennifer

AU - Duncan, Christina

AU - Simeons, Frederick R.C.

AU - Ferguson, Liam

AU - Joji, Halimatu

AU - Read, Kevin D.

AU - Lovell, Scott

AU - Staker, Bart L.

AU - Behr, Marcel A.

AU - Pilli, Ronaldo A.

AU - Couñago, Rafael M.

PY - 2024/11/14

Y1 - 2024/11/14

N2 - Nontuberculous mycobacteria (NTM) are emerging human pathogens linked to severe pulmonary diseases. Current treatments involve the prolonged use of multiple drugs and are often ineffective. Bacterial dihydrofolate reductase (DHFR) is a key enzyme targeted by antibiotics in Gram-negative bacterial infections. However, existing DHFR inhibitors designed for Gram-negative bacteria often fail against mycobacterial DHFRs. Here, we detail the rational design of NTM DHFR inhibitors based on P218, a malarial DHFR inhibitor. We identified compound 8, a 2,4-diaminopyrimidine exhibiting improved pharmacological properties and activity against purified DHFR, and whole cell cultures of two predominant NTM species: Mycobacterium avium and Mycobacterium abscessus. This study underscores the potential of compound 8 as a promising candidate for the in vivo validation of DHFR as an effective treatment against NTM infections.

AB - Nontuberculous mycobacteria (NTM) are emerging human pathogens linked to severe pulmonary diseases. Current treatments involve the prolonged use of multiple drugs and are often ineffective. Bacterial dihydrofolate reductase (DHFR) is a key enzyme targeted by antibiotics in Gram-negative bacterial infections. However, existing DHFR inhibitors designed for Gram-negative bacteria often fail against mycobacterial DHFRs. Here, we detail the rational design of NTM DHFR inhibitors based on P218, a malarial DHFR inhibitor. We identified compound 8, a 2,4-diaminopyrimidine exhibiting improved pharmacological properties and activity against purified DHFR, and whole cell cultures of two predominant NTM species: Mycobacterium avium and Mycobacterium abscessus. This study underscores the potential of compound 8 as a promising candidate for the in vivo validation of DHFR as an effective treatment against NTM infections.

UR - http://www.scopus.com/inward/record.url?scp=85207468174&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.4c01594

DO - 10.1021/acs.jmedchem.4c01594

M3 - Article

C2 - 39468773

AN - SCOPUS:85207468174

SN - 0022-2623

VL - 67

SP - 19143

EP - 19164

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 21

ER -

Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against Mycobacterium abscessus and Mycobacterium avium, Two Emerging Human Pathogens

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