In Vitro Activities of Several Diaminomethylpyridopyrimidines against
            <i>Mycobacterium avium</i>
            Complex

Shoen, Carolyn; Choromanska, Olga; Reynolds, Robert C.; Piper, James R.; Johnson, Cheryl A.; Cynamon, Michael H.

doi:10.1128/aac.42.12.3315

Cited by 10 publications

(6 citation statements)

References 9 publications

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“…However, there are some flaws for these drugs such as: (i) the therapeutic efficacy of RBT against MDR-TB is somewhat flawed because of the anti-RBT cross-resistance, which is acquired by the majority of RFP-resistant MTB isolates [33]. Similar data are also reported for RPT and RLZ [20,34]; (ii) all the FQs possess only modest antituberculous activity in treating TB, whereas quinolone-resistant MTB strains are rapidly increasing [30,32,[35][36][37][38]. In addition, although a number of new FQs have been synthesized and developed as chemotherapeutic drugs against common bacterial infections (e.g., sitafloxacin, gatifloxacin, moxifloxacin, grepafloxacin, WQ-3034, HSR-903, T-3811, etc.…”

Section: Introductionmentioning

confidence: 74%

New Derivatives of BM212: A Class of Antimycobacterial Compounds Based on the Pyrrole Ring as a Scaffold

Biava¹,

Porretta²,

Manetti³

2007

MRMC

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During our investigation in the area of antimycobacterial agents, we have identified the 1,5-(4-chlorophenyl)-2-methyl-3-(4-methylpiperazin-1-yl)methyl-1H-pyrrole (BM212) as the lead compound for a new class of antimycobacterial pyrrole derivatives with potent in vitro activity against mycobacteria and with low cytotoxicity. We have also identified the salient structural features of BM212, while structure-activity relationships (SAR) and molecular modeling studies on pyrrole compounds allowed us to design and synthesize additional analogues. Among them, seven compounds revealed a very high activity (better than that of BM212 toward mycobacteria) and a very interesting protection index, comparable to that of reference compounds, such as isoniazid, streptomycin and rifampin.

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Section: Introductionmentioning

confidence: 74%

New Derivatives of BM212: A Class of Antimycobacterial Compounds Based on the Pyrrole Ring as a Scaffold

Biava¹,

Porretta²,

Manetti³

2007

MRMC

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“…gondii may be useful as drugs against M . avium complex has recently been suggested in two other reports. 14b, …”

Section: Biochemical and Biological Assaysmentioning

confidence: 84%

Structure-Based Design of Selective Inhibitors of Dihydrofolate Reductase: Synthesis and Antiparasitic Activity of 2,4-Diaminopteridine Analogues with a Bridged Diarylamine Side Chain

et al. 1999

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As part of a larger search for potent as well as selective inhibitors of dihydrofolate reductase (DHFR) enzymes from opportunistic pathogens found in patients with AIDS and other immune disorders, N-[(2,4-diaminopteridin-6-yl)methyl]dibenz[b,f]azepine (4a) and the corresponding dihydrodibenz[b,f]azepine, dihydroacridine, phenoxazine, phenothiazine, carbazole, and diphenylamine analogues were synthesized from 2, 4-diamino-6-(bromomethyl)pteridine in 50-75% yield by reaction with the sodium salts of the amines in dry tetrahydrofuran at room temperature. The products were tested for the ability to inhibit DHFR from Pneumocystis carinii (pcDHFR), Toxoplasma gondii (tgDHFR), Mycobacterium avium (maDHFR), and rat liver (rlDHFR). The member of the series with the best combination of potency and species selectivity was 4a, with IC(50) values against the four enzymes of 0. 21, 0.043, 0.012, and 4.4 microM, respectively. The dihydroacridine, phenothiazine, and carbazole analogues were also potent, but nonselective. Of the compounds tested, 4a was the only one to successfully combine the potency of trimetrexate with the selectivity of trimethoprim. Molecular docking simulations using published 3D structural coordinates for the crystalline ternary complexes of pcDHFR and hDHFR suggested a possible structural interpretation for the binding selectivity of 4a and the lack of selectivity of the other compounds. According to this model, 4a is selective because of a unique propensity of the seven-membered ring in the dibenz[b,f]azepine moiety to adopt a puckered orientation that allows it to fit more comfortably into the active site of the P. carinii enzyme than into the active site of the human enzyme. Compound 4a was also evaluated for the ability to be taken up into, and retard the growth of, P. carinii and T. gondii in culture. The IC(50) of 4a against P. carinii trophozoites after 7 days of continuous drug treatment was 1.9 microM as compared with previously observed IC(50) values of >340 microM for trimethoprim and 0.27 microM for trimetrexate. In an assay involving [(3)H]uracil incorporation into the nuclear DNA of T. gondii tachyzoites as the surrogate endpoint for growth, the IC(50) of 4a after 5 h of drug exposure was 0.077 microM. The favorable combination of potency and enzyme selectivity shown by 4a suggests that this novel structure may be an interesting lead for structure-activity optimization.

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“…Similarly, Rosowsky et al synthesized 2,4-diaminopteridine analogues with a bridged diarylamine side chain and found that the compound having seven-membered ring in the dibenz[b,f]azepine moiety was more selective and most active against M. avium DHFR [19]. With the same motivation, Shoen et al synthesized 2,4-diamino-5-methyl-5-deazapteridines (DMDP) having structures similar to the trimetrexate/piritrexim and identified their antimycobacterial activity against M. avium complex (MAC) [20], in the continuation Suling et al established the DMDPs activity and selectivity towards the DHFR of MAC/Human [21]. Additionally, Meyer et al [22] and Gerum et al [23] also identified WR99210 (1,3,5-triazine derivative) and its analogues as potent inhibitors of MAC and M. tuberculosis DHFR, respectively.…”

Section: Introductionmentioning

confidence: 94%

Discovery of new 1,3,5-triazine scaffolds with potent activity against Mycobacterium tuberculosis H37Rv

Sunduru

Gupta

Chaturvedi

et al. 2010

European Journal of Medicinal Chemistry

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In Vitro Activities of Several Diaminomethylpyridopyrimidines against Mycobacterium avium Complex

Cited by 10 publications

References 9 publications

New Derivatives of BM212: A Class of Antimycobacterial Compounds Based on the Pyrrole Ring as a Scaffold

New Derivatives of BM212: A Class of Antimycobacterial Compounds Based on the Pyrrole Ring as a Scaffold

Structure-Based Design of Selective Inhibitors of Dihydrofolate Reductase: Synthesis and Antiparasitic Activity of 2,4-Diaminopteridine Analogues with a Bridged Diarylamine Side Chain

Discovery of new 1,3,5-triazine scaffolds with potent activity against Mycobacterium tuberculosis H37Rv

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