Antibacterial Activity of a Series of N2,N4-Disubstituted Quinazoline-2,4-diamines

Horn, Kurt S. Van; Burda, Whittney N.; Fleeman, Renee; Shaw, Lindsey N.; Manetsch, Roman

doi:10.1021/jm500039e

Cited by 91 publications

(67 citation statements)

References 19 publications

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“…Intermediates 5a−f were obtained from reaction of 2,4-dichloroquinazoline with various amines under basic condition of CH 3 COONa. 13 Then, 5a−f reacted with 1H-pyrazol-4-amine at high temperature to give target molecules 6a−f. The 4-amino-(1H)-pyrazole derivatives were screened for their in vitro kinase inhibitory activities toward JAK1, JAK2, and JAK3 at 10, 1, and 0.1 μM and 40 and 20 nM.…”

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confidence: 99%

Design, Synthesis, and Antitumor Evaluation of 4-Amino-(1H)-pyrazole Derivatives as JAKs Inhibitors

Liang

Zang

Zhu

et al. 2016

ACS Med. Chem. Lett.

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Abnormalities in the JAK/STAT signaling pathway lead to many diseases such as immunodeficiency, inflammation, and cancer. Herein, we designed and synthesized a series of 4-amino-(1H)-pyrazole derivatives as potent JAKs inhibitors for cancer treatment. Results from in vitro protein kinase inhibition experiments indicated that compounds 3a−f and 11b are potent JAKs inhibitors. For example, the IC 50 values of compound 3f against JAK1, JAK2, and JAK3 were 3.4, 2.2, and 3.5 nM, respectively. In cell culture experiments, compound 3f showed potent antiproliferative activity against various cell lines (PC-3, HEL, K562, MCF-7, and MOLT4) at low micromolar levels, while compound 11b showed selective cytotoxicity at submicromolar levels against HEL (IC 50 : 0.35 μM) and K562 (IC 50 : 0.37 μM) cell lines. It is worth noting that both 3f and 11b showed more potent antiproliferative activities than the approved JAKs inhibitor Ruxolitinib. KEYWORDS: JAKs, Inhibitors, 4-Amino-(1H)-pyrazole, Anticancer T he JAK/STAT signaling pathway plays critical roles in immunity, hematopoiesis, and cell growth.1 Abnormalities in the JAK/STAT signaling pathway lead to many diseases such as immunodeficiency, inflammation, and cancers.2 Constitutive activations of JAKs are correlated to oncogenesis. Dysregulation of JAK2 is discovered in patients with myeloproliferative neoplasms and childhood T cell acute lymphoblastic leukemia. 3Several hematologic malignancies including malignant lymphoma and myeloproliferative disorders are associated with mutations of JAK2.4 Some cytokines and growth factors bind to their receptors and then stimulate JAKs for the phosporylation of STAT3, which is a potential target for anticancer therapy. 6 Thus, the JAK/STAT signaling pathway is a promising antitumor target.Inhibitors of JAKs are widely explored for treatment of immunodeficiency, inflammation, and cancer. Among the synthetic JAK inhibitors for the treatment of cancer identified to date (Figure 1), Ruxolitinib (Incyte's Jakafi) was approved by the US Food and Drug Administration (FDA) in 2013 for the treatment of myelofibrosis, a rare bone marrow cancer. Besides, it is in phase III clinical trials for the treatment of metastatic pancreatic cancer and phase II clinical trials for the treatment of multiple myeloma, leukemia, and colon cancer. 7 There are several other JAKs inhibitors in clinical trials for cancer treatment (Figure 1). JAK2 inhibitor AZD1480 can inhibit STAT5 signaling in prostate cancer cells and then effectively inhibit castration-resistant growth of prostate cancer.8 JAK2 inhibitor TG101348 blocks JAK/STAT signaling leading to suppression of proliferation and induction of apoptosis and is used for the treatment of myelofibrosis.9 JAKs inhibitors Momelotinib and

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confidence: 99%

Design, Synthesis, and Antitumor Evaluation of 4-Amino-(1H)-pyrazole Derivatives as JAKs Inhibitors

Liang

Zang

Zhu

et al. 2016

ACS Med. Chem. Lett.

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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: 85%

“…Our group has recently shown the utility of N 2 ,N 4 -disubstituted quinazoline-2,4-diamines for the treatment of S. aureus infections (18). 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.…”

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confidence: 99%

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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“…The residue was treated with nhexane, the crude product was collected by filtration, washed on the filter with EtOH and dried under reduced pressure. _____________________________________________________________________________________________ 2017/34 61 D. [2][3][4]2, J = 7.4,CH3), 0.74 (t, 3H, 3 J = 6.8, CH3). 13 C-NMR (DMSO-d6), δ (ppm): 161.…”

Section: Synthesis Of Compounds 6a-g (General Method)mentioning

confidence: 99%

“…N 2 , N 4 -disubstituted quinazoline-2,4-diamines were also found to display antiparasitic and antileishmanial activity [3]. Additionally, they exhibit promising antibacterial activity against multidrug resistant Staphylococcus aureus [4]. Another derivative of N 2 ,N 4 -disubstituted quinazoline-2,4-diamines is in phase I clinical trials in patients with multiple myeloma and solid tumors [5].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 4-Alkylamino-2-Triazolylquinazolines

Goliškina¹,

Cīrule²,

Bizdēna³

et al. 2017

Materials Science and Applied Chemistry

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Antibacterial Activity of a Series of N²,N⁴-Disubstituted Quinazoline-2,4-diamines

Cited by 91 publications

References 19 publications

Design, Synthesis, and Antitumor Evaluation of 4-Amino-(1H)-pyrazole Derivatives as JAKs Inhibitors

Design, Synthesis, and Antitumor Evaluation of 4-Amino-(1H)-pyrazole Derivatives as JAKs Inhibitors

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

Synthesis of 4-Alkylamino-2-Triazolylquinazolines

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Antibacterial Activity of a Series of N2,N4-Disubstituted Quinazoline-2,4-diamines

Cited by 91 publications

References 19 publications

Design, Synthesis, and Antitumor Evaluation of 4-Amino-(1H)-pyrazole Derivatives as JAKs Inhibitors

Design, Synthesis, and Antitumor Evaluation of 4-Amino-(1H)-pyrazole Derivatives as JAKs Inhibitors

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

Synthesis of 4-Alkylamino-2-Triazolylquinazolines

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Antibacterial Activity of a Series of N²,N⁴-Disubstituted Quinazoline-2,4-diamines

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