Structure guided generation of thieno[3,2-d]pyrimidin-4-amine Mycobacterium tuberculosis bd oxidase inhibitors

Abstract

Screening for inhibitors of Cyt-bd in Mycobacterium bovis BCG and Mycobacterium tuberculosis revealed thieno[3,2-d]pyrimidine (7) which through SAR efforts resulted in an improved analogue (19) of this scaffold.

Syntheses and Structure–Activity Relationships of N-Phenethyl-Quinazolin-4-yl-Amines as Potent Inhibitors of Cytochrome bd Oxidase in Mycobacterium tuberculosis

“…To gain greater insight on the activity of these compounds, they were re-screened against the clinical Mtb isolate N0145 strain. As observed previously with the thieno [3,2-d]pyrimidin-4amine class of cyt-bd oxidase inhibitors [13], these compounds displayed greatly improved activity against the Mtb clinical isolate likely due to lower expression of cyt-bd within clinical isolates as compared to lab-adapted strains like H37Rv [12]. Two compounds, 7a and 12a, from the first set were more active than or comparable in activity to aurachin D (0.1 and 1.1 µM vs. 1.5 µM, respectively).…”

“…The reactions were monitored by TLC on precoated Merck 60 F254 silica gel plates and visualized using UV light (254 nm). All compounds were analyzed for purity by HPLC and characterized by 1 H and 13 C NMR using a Bruker Ascend Avance III HD Spectrometer (500 MHz). Chemical shifts are reported in ppm (δ) relative to the residual solvent peak in the corresponding spectra; chloroform δ 7.27 and δ 77.23, methanol δ 3.31 and δ 49.00 and coupling constants (J) are reported in hertz (Hz) (where, s = singlet, bs = broad singlet, d = doublet, dd = double doublet, bd = broad doublet, ddd = double doublet of doublet, t = triplet, tt = triple triplet, q = quartet, m = multiplet) and analyzed using MestreNova NMR data processing.…”

“…mp 128.9-129.7 • C; 1 H (500 MHz, CDCl 3 ) δ ppm 8.69 (s, 1H), 7.60 (dd, J = 9.1, 5.6 Hz, 1H), 7.49 (dd, J = 9.8, 2.5 Hz, 1H), 7.32-7.26 (m, 2H), 7.24-7.17 (m, 3H), 5.74 (br.s, 1H), 3.96 (dt, J = 6.9, 5.9 Hz, 2H), 3.07 (t, J = 7.0 Hz, 2H). 13…”

“…Herein, we report our initial design, synthesis, and activity assessment of various quinazoline compounds for activity against cyt-bd of Mycobacterium bovis BCG and Mycobacterium tuberculosis. [13], ND-11992 (2) [12], and N-phenethylquinazolin-4-amine (3) screening hit. The selective cyt-bcc:aa3 inhibitor Q203 (4) [10] and natural cyt-bd inhibitor aurachin D [7].…”

“…The selective cyt-bcc:aa3 inhibitor Q203 (4) [10] and natural cyt-bd inhibitor aurachin D [7]. [13], ND-11992 (2) [12], and N-phenethylquinazolin-4-amine (3) screening hit. The selective cyt-bcc:aa 3 inhibitor Q203 (4) [10] and natural cyt-bd inhibitor aurachin D [7].…”