Selective Inhibitors of Candida albicans Dihydrofolate Reductase: Activity and Selectivity of 5-(Arylthio)-2,4-diaminoquinazolines

Abstract

The recent increase in fungal infections, especially among AIDS patients, has resulted in the need for more effective antifungal agents. In our search for such agents, we focused on developing compounds which inhibit fungal dihydrofolate reductase (DHFR). A series of 25 5-(arylthio)-2,4-diaminoquinazolines were synthesized as potentially selective inhibitors of Candida albicans DHFR. The majority of the compounds were potent inhibitors of C. albicans DHFR and much less active against human DHFR. High selectivity, as defined by the ratio of the I50 values for human and C. albicans DHFR, was achieved by compounds with bulky and rigid 4-substituents in the phenylthio moiety. For example, 5-[(4-morpholinophenyl)thio]-2,4-diaminoquinazoline displayed a selectivity ratio of 540 and was the most selective inhibitor synthesized to date. Substitution in the 2- or 3-position of the 5-phenylthio group provided only marginal selectivity. 6-Substituted-5-[(4-tert-butylphenyl)thio]-2,4-diaminoquinazolines showed potent activity against the C. albicans enzyme but were equally active against human DHFR. Most of the selective compounds were also good inhibitors of C. albicans cell growth, with minimum inhibitory concentration values as low as 0.05 microgram/ mL.

On the use of PIPSA to Guide Target‐Selective Drug Design

“…[5] Although known clinical drugs against DHFR show weak activity against C. albicans, [5] potent, selective inhibitors of C. albicans DHFR have been reported. [6,7] Their selectivity for C. albicans versus human DHFR has been ascribed in part to differences in protein-ligand hydrogen bonding. Such differences can be detected by analysis of the protein electrostatic potentials.…”

X-ray Crystallographic Studies of Candida albicans Dihydrofolate Reductase

“…This difference in the cleft geometry might provide a basis for selective inhibition. Indeed, a series of DHFR inhibitors that do show significant selectivity for C. albicans DHFR versus the human enzyme was recently reported (49). Some of those inhibitors, represented by Structure 1, were found to bind to the fungal enzyme in a manner that forces the arylthio substituent against the side of the binding cleft (near Ile 62 ) where the human and fungal DHFR protein structures differ in backbone geometry.…”

Synthesis and Characterization of Bis-quinazolines from Linear Tetra-amines Involving 2-(Aminomethyl)benzenamine with Aldehydes

“…Quinazolines have been widely studied in recent years due to their wide range of chemotherapeutic activities including antiviral [1], antibacterial [2,3], antifungal [4,5], antimalarial [6], antitumorals [7][8][9], antihypertensive [10], diuretic [11,12], inhibitors of cyclin-dependent kinases [13], anticonvulsant [14], ghrelin receptor antagonists [15], antiinflammatory, analgesic, and COX-II inhibitors [16,17]. Hence, the synthesis and research of new quinazolines is of great interest.…”

“…Hence, the synthesis and research of new quinazolines is of great interest. We report the synthesis and characterization of seven derivatives of diastereoisomers of Bis-quinazolines (1,2,3,4,5,6, and 7) derived of L 1 , L 2 , and L 3 with 2-nitrobenzaldehyde, 2-hydroxy-3-methoxybenzaldehyde, and 2-hydroxybenzaldehyde. The linear tetra-amines, L 1 , L 2 , and L 3 , were synthesized by condensation of 1,2-diaminoethane, 1,3-diaminopropane, and/or 1,4-diaminobutane with 2-nitrobenzaldehyde followed by reduction of imine bonds of the resulting products with NaBH 4 and then reduction of the nitro groups using zinc and ammonium chloride (Scheme 1).…”