Novel 2,4-diaminopyrimidines bearing N,N-disubstituted aminomethyl residues at the 5-position were designed as dihydrofolate reductase (DHFR) inhibitors. These compounds were obtained by treatment of 1-[(2,4-diamino-5-pyrimidinyl)methyl]pyridinium bromide with secondary amines in a polar solvent and in the presence of triethylamine at room temperature. The procedure was found to be very efficient and suitable for application in high-throughput synthesis. In addition, we found that high-throughput screening for enzymatic and in vitro antibacterial activity could be performed on crude reaction mixtures, thus avoiding any purification step. Over 1200 proprietary secondary amines were selected for high-throughput synthesis, based on structural and diversity-related criteria, and the resulting products were submitted to high-throughput screening. A greater number of hits, and significantly more active compounds, were obtained through structure-based library design than through diversity-based library design. Different classes of inhibitors of DHFR were identified in this way, including compounds derived from di-, tri-, and tetracyclic amines. In general, these products showed high activity against the enzymes derived from both TMP-sensitive and TMP-resistant Streptococcus pneumoniae. Some compounds possessed appreciable selectivity for the bacterial over the human enzyme, whereas other compounds were not at all selective. In most cases, active enzyme inhibitors also displayed antibacterial activity.
Abstract: The rise in the incidence of fungal infections over the past two to three decades, particularly those caused by opportunistic pathogens in immune-compromised patients, has strengthened the need for new antifungal drugs. Up to only 30 years ago the choice of systemically available antimycotics was between two drugs, amphotericin B and 5-flurocytosine, neither of which was satisfactory. Then a series of inhibitors of the biosynthesis of ergosterol, the major sterol of the fungal cell membrane, were found to have excellent antifungal activity, improved safety, and some were also active after oral or parenteral application. Starting with miconazole and ketoconazole, and improving through fluconazole and itraconazole, the imidazole and triazole inhibitors of lanosterol Cl4u-demethylation have been the most successful. Other steps in the linear sterol biosynthesis pathway are inhibited by the allylamines naftifine and terbinafine, and the morpholine derivative amorolphine, which have also improved the therapy of superficial mycoses. The discovery, mode of action, current clinical application and future possibilities for these drugs is reviewed. The status and potential of SBI antifungals in development, exclusively azoles, is discussed. Attempts to discover non-azole inhbitors of lanosterol C14u-demethylase are mentioned, as well as current work on other targets in the ergosterol biosynthetic pathway. Particular attention is paid to the oxidsqualene cyclase, which has been extensively studied. The current knowledge about resistance to antifungal agents is reviewed.
The synthesis and biological evaluation of three new sulfur-substituted oxidosqualene (OS) analogues (1-3) are presented. In these analogues, C-11, C-15, or C-18 in the OS skeleton was replaced by sulfur. The sulfur position in the OS skeleton was chosen to disrupt one or more key processes involved in cyclization: (a) the folding of the B-ring into a boat conformation, (b) the anti-Markovnikov cyclization leading to the C-ring, or (c) the formation of the D-ring during the lanosterol biosynthesis. Enzyme inhibition kinetics using homogeneous mammalian oxidosqualene cyclases (OSC) were also examined for the previously reported S-19 analogue 4. The four analogues were potent inhibitors of mammalian OSCs (IC50 = 0.05-2.3 microM for pig and rat liver OSC) and fungal cell-free Candida albicans OSC (submicromolar IC50 values). In particular, the S-18 analogue 3 showed the most potent inhibition toward the rat liver enzyme (IC50 = 50 nM) and showed potent, selective inhibition against the fungal enzyme (IC50 = 0.22 nM, 10-fold more potent than the S-19 analogue 4). Thus, 3 is the most potent OSC inhibitor known to date. The Ki values ranged from 0.5 to 4.5 microM for pig OSC, with 3 and 4 showing about 10-fold higher potency for rat liver OSC. Interestingly, the S-18 analogue 3 showed time-dependent irreversible inhibition with homogeneous pig liver OSC (kinact = 0.06 min-1) but not with rat OSC.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSynthesis of (6E)-8-Thia- and (14E)-13-Thia-2,3-oxidosqualene: Inhibitors of 2,3-Oxidosqualene-Lanosterol CyclaseYi Feng Zheng, Allan C. Oehlschlager, and Peter G. HartmanCite this: J. Org. Chem. 1994, 59, 19, 5803–5809Publication Date (Print):September 1, 1994Publication History Published online1 May 2002Published inissue 1 September 1994https://pubs.acs.org/doi/10.1021/jo00098a048https://doi.org/10.1021/jo00098a048research-articleACS PublicationsRequest reuse permissionsArticle Views373Altmetric-Citations29LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
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