Nonclassical 2,4-diamino-6-(aminomethyl)-5,6,7,8-tetrahydroquinazoline antifolates: synthesis and biological activities

Gangjee, Aleem; Zaveri, Nurulain T.; Kothare, Mohi; Queener, Sherry F.

doi:10.1021/jm00018a027

Cited by 23 publications

(35 citation statements)

References 15 publications

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“…The indoline group could additionally interact with a region of the active site near the cofactor position that was not expected to be exploited by 15a. The improved selectivity of 15a compared to TMQ was explained by differences in the conformations of 15a and TMQ similar to that suggested in the model [94].…”

Section: Inhibitors Of Pneumocystis Carinii (Pc) Dhfr Toxoplasma Gonsupporting

confidence: 67%

“…Partial saturation of the B ring of TMQ generated the 6-substituted 2,4-diamino tetrahydroquinazoline, 15a (Fig. 5) with a chiral centre at C6 that could orient the 6-substituent in an axial or equatorial conformation [94]. Since the side chain and its conformation(s) were important for both selectivity as well as potency for DHFR inhibition, Gangjee et al [ 94] reasoned that compounds which oriented their side chains differently from that of TMQ in hDHFR [95] could be selective and potent inhibitors of pcDHFR and tgDHFR.…”

Section: Inhibitors Of Pneumocystis Carinii (Pc) Dhfr Toxoplasma Gonmentioning

confidence: 99%

“…5) with a chiral centre at C6 that could orient the 6-substituent in an axial or equatorial conformation [94]. Since the side chain and its conformation(s) were important for both selectivity as well as potency for DHFR inhibition, Gangjee et al [ 94] reasoned that compounds which oriented their side chains differently from that of TMQ in hDHFR [95] could be selective and potent inhibitors of pcDHFR and tgDHFR. Energy minimization of the different conformations of 15a using SYBYL [96] and superimposition on TMQ with the pyrimidine rings overlapped indicated that the side chain conformations of the tetrahydroquinazoline analogs were different from that of TMQ.…”

Section: Inhibitors Of Pneumocystis Carinii (Pc) Dhfr Toxoplasma Gonmentioning

confidence: 99%

“…Of these compounds, 19e-g were conformationally restricted analogs where the methoxy-substituted phenyl side chain was locked in a trans configuration. Reduced 5,6,7,8-tetrahydro-5,10-dideaza analogs 19k and 19l were synthesized based on the improved potency and selectivity for pcDHFR and tgDHFR in the 2,4-diamino-6-substituted tetrahydroquinazoline series, 19a-g [94]. The synthesis involved a common 2,4-bis(pivaloylamino)-6-bromopyrido [2,3-d]pyrimidine intermediate, prepared from 2,4,6-triaminopyrimidine and bromomalonaldehyde, followed by protection of the 2-and 4-amino groups.…”

Section: -Substituted 24-diamino Pyrido[23-d]pyrimidinesmentioning

confidence: 99%

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Dihydrofolate Reductase as a Target for Chemotherapy in Parasites

Gangjee¹,

Kurup²,

Namjoshi³

2007

CPD

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Opportunistic infections are known to cause morbidity and mortality in immunocompromised individuals. In addition, serious infections due to several parasites are also known to affect the quality and duration of life in normal individuals. The importance of dihydrofolate reductase (DHFR) in parasitic chemotherapy arises from its function in DNA biosynthesis and cell replication. DHFR catalyzes the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF), an essential cofactor in the biosynthesis of thymidylate monophosphate (dTMP). Inhibition of DHFR leads to a deficiency of dTMP since DHF cannot be recycled, and thus causes inhibition of cell growth. Methotrexate (MTX) and aminopterin (AMT) were among the first known classical inhibitors of DHFR. Trimethoprim (TMP) and pyrimethamine (PYR) are among the first known non classical inhibitors of DHFR. TMP and PYR are selective but weak inhibitors of DHFR from several parasitic organisms and coadministration of sulfonamides is required to provide synergistic effects for clinical utility. Unfortunately, the side effects associated with sulfa drugs in this combination often result in cessation of therapy. Trimetrexate (TMQ) and piritrexim (PTX) are two potent non classical inhibitors, neither of which exhibit selectivity for pathogen DHFR and must be used with host rescue. However, the current combination therapy suffers from high cost, in addition, several mutations have been reported in the active site of parasitic DHFR rendering the infections refractive to known DHFR inhibitors. The selectivity of TMP is a hallmark in the development of DHFR inhibitors and several efforts have been made to combine the potency of PTX and TMQ with the selectivity of TMP. Thus the structural requirements for DHFR inhibition are of critical importance in the design of antifolates for parasitic chemotherapy. Structural requirements for inhibition have been studied extensively and novel agents that exploit the differences in the active site of human and parasitic DHFR have been proposed. This review discusses the synthesis and structural requirements for selective DHFR inhibition and their relevance to parasitic chemotherapy, since 1995.

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Section: Inhibitors Of Pneumocystis Carinii (Pc) Dhfr Toxoplasma Gonsupporting

confidence: 67%

Section: Inhibitors Of Pneumocystis Carinii (Pc) Dhfr Toxoplasma Gonmentioning

confidence: 99%

Section: Inhibitors Of Pneumocystis Carinii (Pc) Dhfr Toxoplasma Gonmentioning

confidence: 99%

Section: -Substituted 24-diamino Pyrido[23-d]pyrimidinesmentioning

confidence: 99%

See 2 more Smart Citations

Dihydrofolate Reductase as a Target for Chemotherapy in Parasites

Gangjee¹,

Kurup²,

Namjoshi³

2007

CPD

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“…As part of our ongoing research program on heterocyclic compounds, which may serve as leads for designing novel antitumor referred to PD153035 as the leading compound, we were particularly interested in 4-substituted quinazolines [6][7][8][9][10][11][12]. We considered the well-known activity of the quinazoline nucleus in chemotherapy, where many of its substituted derivatives are effective antitumor agents [13][14][15][16]. N N MeO MeO N H Br PD153035…”

mentioning

confidence: 99%

Synthesis and biological activity of novel N-substituted 4-amino-6,7,8-trimethoxyquinazoline compounds

Liu

Sun

et al. 2007

Chem Heterocycl Comp

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trimethoxyquinazoline has been synthesized from natural gallic acid by a novel route. Their structures have been verified by elemental analysis and IR, 1 H, and 13 C NMR spectroscopy. The title compounds have been evaluated for their in vitro antiproliferative activities against some cancer cells by the MTT method. Unfortunately, most of the compounds tested have exhibited a weaker anticancer activity than the reference standard drug PD153035.Recently it has been shown that quinazoline compounds exhibit promising biological activity for medicinal or pesticidal use [1][2][3][4][5]. As part of our ongoing research program on heterocyclic compounds, which may serve as leads for designing novel antitumor referred to PD153035 as the leading compound, we were particularly interested in 4-substituted quinazolines [6][7][8][9][10][11][12]. We considered the well-known activity of the quinazoline nucleus in chemotherapy, where many of its substituted derivatives are effective antitumor agents [13][14][15][16]. N N MeO MeO N H Br PD153035Furthermore, the more recent data reported that a broad class of quinazolines also acts as potent and highly selective inhibitors of epidermal growth factor receptor (EGFR) or epidermal growth factor receptor tyrosine kinase (EGFR-TK) [17][18][19][20][21]; the members of this class are expected to have great therapeutic potential in the treatment of malignant and nonmalignant epithelial diseases [22,23]. In view of these facts and in order to

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ELECT++: Faster conformational search method for docking flexible molecules using molecular similarity

Makino

Kuntz

1998

J. Comput. Chem.

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We have developed a program, ELECT++ (Effective LEssening of Conformations by Template molecules in C++), to speed up the conformational search for small flexible molecules using the similar property principle. We apply this principle to molecular shape and, importantly, to molecular flexibility. After molecules in a database are clustered according to flexibility and shape (FCLUST++), additional reagents are generated to screen the conformational space of molecules in each cluster (TEMPLATE++). We call these representative reagents of each cluster template reagents. Template reagents and clustered reagents produce, after reaction, template molecules and clustered molecules, respectively (tREACT++). The conformations of a template molecule are searched in the context of a macromolecular target. Acceptable conformational choices are then applied to all molecules in its cluster, thus effectively biasing conformational space to speed up conformational searches (tSEARCH++). In our incremental search method, it is necessary to calculate the root‐mean‐square deviations (RMSD) matrix of distances between different conformations of the same molecule to reduce the number of conformations. Instead of calculating the RMSD matrix for all molecules in a cluster, the RMSD matrix of a template molecule is chosen as a reference and applied to all the molecules in its cluster. We demonstrate that FCLUST++ clusters the primary amine reagents from the Available Chemicals Directory (ACD) successfully. The program tSEARCH++ was applied to dihydrofolate reductase with virtual molecules generated by tREACT++ using clustered primary amine reagents. The conformational search by the program tSEARCH++ was about 4.8 times faster than by SEARCH++, with an acceptable range of errors. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 1834–1852, 1998

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Nonclassical 2,4-diamino-6-(aminomethyl)-5,6,7,8-tetrahydroquinazoline antifolates: synthesis and biological activities

Cited by 23 publications

References 15 publications

Dihydrofolate Reductase as a Target for Chemotherapy in Parasites

Dihydrofolate Reductase as a Target for Chemotherapy in Parasites

Synthesis and biological activity of novel N-substituted 4-amino-6,7,8-trimethoxyquinazoline compounds

ELECT++: Faster conformational search method for docking flexible molecules using molecular similarity

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