Oxazoles for click chemistry II: synthesis of extended heterocyclic scaffolds

Abstract

New routes to 2, 4, 5-trisubstituted oxazoles were established whereby the substitution pattern was established by the structure of the starting nonsymmetrical acyloins. 2-Chloromethyl-4, 5-disubstituted oxazoles were prepared by refinements of an earlier described process whereby chloroacetyl esters of symmetrical and non-symmetrical acyloins were cyclized using an ammonium acetate/acetic acid protocol. After substitution is effected, the azide moiety is then installed by substitution under mild conditions. While dibrominated and iodinated phenyloxazoles are required for further synthetic elaboration, the cyclization reaction was found to be very sensitive to the relative positions of the halogens in the starting materials.

‘Second-generation’ 1,2,3-triazole-based inhibitors of Porphyromonas gingivalis adherence to oral streptococci and biofilm formation

“…2-Chloromethyl-4,5-diphenyloxazoles 1-3, versatile synthetic intermediates prepared in multi-gram quantities and in modest to good yields by methods previously reported from these laboratories, are the starting points. [23][24][25][26] The chloromethyl oxazoles 1-3 are reacted with 4-aminothiophenol in the presence of sodium hydride in THF to afford the 4-(aminothiophenyl)oxazoles 4-6 in yields ranging from 66% to 85%. Treatment of the (aminothiophenyl) oxazoles 4-6 with sodium nitrite in 10% aqueous HCl and sodium azide (5°C to rt, 16 h) gave the corresponding 4-azidophenylIJoxazolyl)sulfides 7-9 (61-98%) with no interference from the sulfide group.…”

“…[14][15][16][17][18][19][20][21][22] In this report, we describe the syntheses and click reactions of similar 2,4,5-trisubstituted oxazole NITVK mimics. [23][24][25][26] These reacting components are now used in conjunction with sulfinylaryl-and sulfonylaryl-1,2,3-triazole linkers, albeit with the mono-and disubstituted aryl groups acting as the VXXLL structural mimic. Similar to the previous 'first-generation' compounds, the newly formed 1,2,3-triazole linker arising from the click reaction functions as the polar, slightly basic section of the entire peptidomimetic with the phenylsulfinyl or phenylsulfonyl portion allowing several more degrees of conformational freedom in the molecule's overall topology.…”

1,2,3-Triazole-based inhibitors of Porphyromonas gingivalis adherence to oral streptococci and biofilm formation

“…Since the streptococcal NR box-like sequence contains two functional motifs, we envisioned that the design and study of small-molecule, non-peptide based inhibitors of the Mfa/AgI/II interaction encompassed the employment of two synthetic small-molecule scaffolds joined together via the “click” reaction 9,10 . Within the expansive area of nitrogen/oxygen heterocycles, we have identified the 2,4,5-trisubstituted oxazole framework as a starting point for the NITVK-associated inhibitors of Mfa/AgI/II interaction 11–13 and show here that these compounds potently block P. gingivalis adherence to streptococci in vitro when clicked with substituted arylalkynes. As click chemistry involves the classical cycloaddition reaction between an alkyl or aryl azide and an alkyl or aryl alkyne, the oxazoles were functionalized with the azide moiety and an array of arylalkynyl click partners containing hydrophobic groups were chosen for both evaluating the click reactions and exploring and evaluating the minimal structural requirements for the VXXLL mimic.…”

Identification of functional domains of the minor fimbrial antigen involved in the interaction of Porphyromonas gingivalis with oral streptococci

“…To further highlight the functional region(s) of Mfa1, we took advantage of the recently published three‐dimensional structure of Mfa1 (Hall et al, ) to predict putative binding clefts using SiteMap. In addition, a series of in silico docking experiments were conducted using five peptidomimetic compounds that mimic the BAR peptide and were previously shown by Patil et al (Patil et al, , ) to be potent competitive inhibitors of P. gingivalis/S. gordonii adherence.…”