Structure-Based Design of New Dihydrofolate Reductase Antibacterial Agents: 7-(Benzimidazol-1-yl)-2,4-diaminoquinazolines

Lam, Thanh; Hilgers, M.T.; Cunningham, Mark L.; Kwan, Bryan; Nelson, Kirk; Brown-Driver, Vickie; Ong, Voon; Trzoss, Michael; Hough, Grayson W.; Shaw, Karen Joy; Finn, John M.

doi:10.1021/jm401204g

Cited by 66 publications

(39 citation statements)

References 25 publications

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“…The current model prediction is consistent with the experimental finding, demonstrating the validity of the approach. Recently structure-based design has led to the development of new DHFR inhibitors that are potent and selective against Staphylococcus aureus in vitro and in vivo [30], indicating the potential of developing more potent and selective antifolate drugs.…”

Section: Discussionmentioning

confidence: 99%

New small-molecule inhibitors of dihydrofolate reductase inhibit Streptococcus mutans

Zhang

Nguyen

McMichael

et al. 2015

International Journal of Antimicrobial Agents

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Streptococcus mutans is a major aetiological agent of dental caries. Formation of biofilms is a key virulence factor of S. mutans. Drugs that inhibit S. mutans biofilms may have therapeutic potential. Dihydrofolate reductase (DHFR) plays a critical role in regulating the metabolism of folate. DHFR inhibitors are thus potent drugs and have been explored as anticancer and antimicrobial agents. In this study, a library of analogues based on a DHFR inhibitor, trimetrexate (TMQ), an FDA-approved drug, was screened and three new analogues that selectively inhibited S. mutans were identified. The most potent inhibitor had a 50% inhibitory concentration (IC50) of 454.0 ± 10.2 nM for the biofilm and 8.7 ± 1.9 nM for DHFR of S. mutans. In contrast, the IC50 of this compound for human DHFR was ca. 1000 nM, a >100-fold decrease in its potency, demonstrating the high selectivity of the analogue. An analogue that exhibited the least potency for the S. mutans biofilm also had the lowest activity towards inhibiting S. mutans DHFR, further indicating that inhibition of biofilms is related to reduced DHFR activity. These data, along with docking of the potent analogue to the modelled DHFR structure, suggested that the TMQ analogues indeed selectively inhibited S. mutans through targeting DHFR. These potent and selective small molecules are thus promising lead compounds to develop new effective therapeutics to prevent and treat dental caries.

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Section: Discussionmentioning

confidence: 99%

New small-molecule inhibitors of dihydrofolate reductase inhibit Streptococcus mutans

Zhang

Nguyen

McMichael

et al. 2015

International Journal of Antimicrobial Agents

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“…[21][22][23] Trimethoprim and 7-(2-ethoxynaphthalen-1-yl)-6-methylquinazoline-2,4-diamine were used as the references. [20] The obtained scoring functions (Shapegauss, PLP, Chemgauss2, Chemgauss3, Chemscore, OEChemscore, Screenscore, CGO, CGT, Zapbind, Consensus Score) indicated the best possibility of matching into the ligand-protein complex (Table S1 in the Supporting Information).…”

Section: Docking Studies To S Aureus Dihydrofolate Reductasementioning

confidence: 99%

“…[1,5-c]quinazolines are condensed structural analogues of 2,4-diaminoquinazolines, which are reported to have a high selectivity to S. aureus DHFR. [20] The flexible molecular docking study was performed by using the geometry-optimized structure of the investigated compounds into the active site of S. aureus DHFR (4LAE.pdb) with the software package OpenEye. [21][22][23] Trimethoprim and 7-(2-ethoxynaphthalen-1-yl)-6-methylquinazoline-2,4-diamine were used as the references.…”

Section: Docking Studies To S Aureus Dihydrofolate Reductasementioning

confidence: 99%

2‐Heteroaryl‐[1,2,4]triazolo[1,5‐c]quinazoline‐5(6 H)‐thiones and Their S‐Substituted Derivatives: Synthesis, Spectroscopic Data, and Biological Activity

et al. 2015

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In the continuing search for novel, biologically effective heterocyclic agents, several methods for the synthesis of 2‐heteroaryl‐[1,2,4]triazolo[1,5‐c]quinazoline‐5(6 H)‐thiones have been developed: thiolation of oxo derivatives, [5+1] cyclocondensation of [2‐(3‐heteroaryl‐[1,2,4]triazol‐5‐yl)phenyl]amines with carbon disulfide, potassium ethyl xanthogenate, or aryl isothiocyanates, and in situ reaction of 2‐isothiocyanatobenzonitrile with hydrazides. A series of N‐R‐2‐[(2‐heteroaryl‐[1,2,4]triazole‐[1,5‐c]quinazoline‐5‐yl)thio]acetamides were obtained by aminolysis of the corresponding acetic acids and alkylation of potassium thiolates with N‐R‐2‐chloroacetamides. It was established that some potassium thiolates, 4 a–4 d, 4 h, and 4 i, had high antibacterial activity against Staphylococcus aureus with a minimum inhibitory concentration of 12.5 μg mL−1 and minimum bactericidal concentration of 25 μg mL−1, which exceeded the values for trimethoprim. In addition, {2‐[3‐(1 H‐indole‐2‐yl)‐1 H‐1,2,4‐triazol‐5‐yl]phenyl}amine 2 i was investigated in the concentration range 100–0.01 μM at 59 lines of nine cancer cell types, and showed a mean effective concentration at 3.12–7.03 μM and cytotoxic effect at 15.56–67.38 μM. The possible mechanisms of activity were predicted by molecular docking studies to S. aureus dihydrofolate reductase and epidermal growth factor receptor kinase.

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“…Specifically, we have shown them to be active against a library of methicillin-resistant S. aureus (MRSA) isolates, displaying strong bactericidal activities, with limited cytotoxic and hemolytic capacities toward human cells. Mechanism-of-action profiling reveals that much like other quinazoline compounds, they appear to function by targeting bacterial dihydrofolate reductase (18)(19)(20)(21). We have also shown their potential for antibiofilm activity, low frequencies of mutation, and in vivo efficacy using murine models of infection (18).…”

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confidence: 87%

Characterizing the Antimicrobial Activity of N ² , N ⁴ -Disubstituted Quinazoline-2,4-Diamines toward Multidrug-Resistant Acinetobacter baumannii

Fleeman

Horn

Barber

et al. 2017

Antimicrob Agents Chemother

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We previously reported a series of N 2 ,N 4 -disubstituted quinazoline-2,4-diamines as dihydrofolate reductase inhibitors with potent in vitro and in vivo antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) strains. In this work, we extended our previous study to the Gram-negative pathogen Acinetobacter baumannii. We determined that optimized N 2 ,N 4 -disubstituted quinazoline-2,4-diamines are strongly antibacterial against multidrug-resistant A. baumannii strains when the 6-position is replaced with a halide or an alkyl substituent. Such agents display potent antibacterial activity, with MICs as low as 0.5 M, while proving to be strongly bactericidal. Interestingly, these compounds also possess the potential for antibiofilm activity, eradicating 90% of cells within a biofilm at or near MICs. Using serial passage assays, we observed a limited capacity for the development of resistance toward these molecules (4-fold increase in MIC) compared to existing folic acid synthesis inhibitors, such as trimethoprim (64-fold increase) and sulfamethoxazole (128-fold increase). We also identified limited toxicity toward human cells, with 50% lethal doses (LD 50 s) of Յ23 M for lead agents 4 and 5. Finally, we demonstrated that our lead agents have excellent in vivo efficacy, with lead agent 5 proving more efficacious than tigecycline in a murine model of A. baumannii infection (90% survival versus 66%), despite being used at a lower dose (2 versus 30 mg kg Ϫ1 ). Together, our results demonstrate that N 2 ,N 4 -disubstituted quinazoline-2,4-diamines have strong antimicrobial and antibiofilm activities against both Gram-positive organisms and Gram-negative pathogens, suggesting strong potential for their development as antibacterial agents.

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Structure-Based Design of New Dihydrofolate Reductase Antibacterial Agents: 7-(Benzimidazol-1-yl)-2,4-diaminoquinazolines

Cited by 66 publications

References 25 publications

New small-molecule inhibitors of dihydrofolate reductase inhibit Streptococcus mutans

New small-molecule inhibitors of dihydrofolate reductase inhibit Streptococcus mutans

2‐Heteroaryl‐[1,2,4]triazolo[1,5‐c]quinazoline‐5(6 H)‐thiones and Their S‐Substituted Derivatives: Synthesis, Spectroscopic Data, and Biological Activity

Characterizing the Antimicrobial Activity of N ² , N ⁴ -Disubstituted Quinazoline-2,4-Diamines toward Multidrug-Resistant Acinetobacter baumannii

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Structure-Based Design of New Dihydrofolate Reductase Antibacterial Agents: 7-(Benzimidazol-1-yl)-2,4-diaminoquinazolines

Cited by 66 publications

References 25 publications

New small-molecule inhibitors of dihydrofolate reductase inhibit Streptococcus mutans

New small-molecule inhibitors of dihydrofolate reductase inhibit Streptococcus mutans

2‐Heteroaryl‐[1,2,4]triazolo[1,5‐c]quinazoline‐5(6 H)‐thiones and Their S‐Substituted Derivatives: Synthesis, Spectroscopic Data, and Biological Activity

Characterizing the Antimicrobial Activity of N 2 , N 4 -Disubstituted Quinazoline-2,4-Diamines toward Multidrug-Resistant Acinetobacter baumannii

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Characterizing the Antimicrobial Activity of N ² , N ⁴ -Disubstituted Quinazoline-2,4-Diamines toward Multidrug-Resistant Acinetobacter baumannii