ChemInform Abstract: High‐Affinity Inhibitors of Dihydrofolate Reductase: Antimicrobial and Anticancer Activities of 7,8‐Dialkyl‐1,3‐diaminopyrrolo(3,2‐f) quinazolines with Small Molecular Size.

Abstract

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Propargyl-Linked Antifolates are Dual Inhibitors of Candida albicans and Candida glabrata

“…Interestingly, similar trends are apparent in the Glaxo work. 11 In that work, potent compounds were also amphipathic with hydrophobic domains attached to the diaminopyrimidine ring; potency was decreased when these domains were di-or trimethoxybenzyl groups. The differences in activity between C. albicans and C. glabrata may relate to differences in the composition of their cell walls.…”

“…According to the general Suzuki coupling procedure, ketone 7 (0.50 g, 2.10 mmol), pyridine-4-boronic acid (0.54 g, 4.36 mmol), Cs 2 CO 3 (2.15 g, 6.55 mmol), Pd(PPh 3 ) 2 Cl 2 (0.15 g, 0.22 mmol, 10% Pd), and anhydrous dioxane (6 mL) were heated at 80 °C for 12 h (overnight). Following the general workup and flash chromatography (SiO 2 , 20 g, 50% EtOAc/hexanes), biaryl ketone 10 was obtained as a pale white solid (0.45 g, 89%): TLC R f = 0.2 (50% EtOAc/hexanes); mp 88.8−92; 1 H NMR (500 MHz, CDCl 3 ) δ 8.72 (d, J = 5.3 Hz, 2H), 7.86 (d, J = 7.9 Hz, 1H), 7.55−7.52 (m, 2H), 7.27 (dd, J = 8.0, 1.3 Hz, 1H), 7.20 (s, 1H), 4.02 (s, 3H), 2.67 (s, 3H); 13 1-[3-Methoxy-4′-(tetrahydro-pyran-2-yloxy)-biphenyl-4-yl]-ethanone (11). According to the general Suzuki coupling procedure, ketone 7 (0.49 g, 2.17 mmol), 4-(tetrahydro-2H-pyran-2-yloxy)phenylboronic acid (0.96 g, 4.34 mmol), Cs 2 CO 3 (2.12 g, 6.51 mmol), Pd(PPh 3 ) 2 Cl 2 (0.15 g, 0.22 mmol, 10% Pd), and anhydrous dioxane (6 mL) was heated at 80 °C for 14 h (overnight).…”

“…The researchers concluded that there was no relationship between activity and inhibitor size or lipophilicity but that differences in transport phenomenon could still play an important role in antifungal activity. 11 More recently, a German company 12 reported a group of potent C. albicans DHFR inhibitors based on a benzyl(oxy)pyrimidine scaffold. However, these compounds did not exhibit in vitro antifungal activity.…”

“…It is widely recognized that the development of antimetabolites targeting C. albicans can be complicated by pronounced inconsistencies between target inhibition and antifungal activity. − Attempts to study whether the cell wall or membrane permeability affects the uptake of six unrelated antibiotics targeting intracellular proteins failed to derive a direct relationship . These same inconsistencies have also complicated the development of antifungal antifolates.…”

“…Although the Glaxo effort produced potent, albeit nonselective inhibitors with good antifungal activity, lead optimization of the antifolates against C. albicans was hindered by a lack of correlation between enzyme inhibition and antifungal activity. The researchers concluded that there was no relationship between activity and inhibitor size or lipophilicity but that differences in transport phenomenon could still play an important role in antifungal activity . More recently, a German company reported a group of potent C. albicans DHFR inhibitors based on a benzyl­(oxy)­pyrimidine scaffold.…”