Targeting the hydrophobic channel of NNIBP: discovery of novel 1,2,3-triazole-derived diarylpyrimidines as novel HIV-1 NNRTIs with high potency against wild-type and K103N mutant virus

Abstract

Novel 1,2,3-triazole-derived diarylpyrimidines were discovered as potent HIV-1 NNRTIs.

Druggability modification strategies of the diarylpyrimidine‐type non‐nucleoside reverse transcriptase inhibitors

“…66 Compared with the BP‐DAPYs, all the alkyne containing compounds (e.g., 62 – 63 ) displayed partly reducing antiviral activity (Table 7), which was suspected that this channel was unfavorable for substitutions with high steric hindrance. Introducing a hydrophilic triazole into the biphenyl moiety by a classic click reaction showed acceptable activity against WT HIV‐1 strain with EC 50 values of 0.013–5.62 μM 66 . Compounds 64 – 65 confirmed a significant improvement on the pH‐independent water solubility.…”

“…It is well‐known that different substituents will lead to different diherdral angles of the biphenyl moiety 64,65 . Adjusting the substituents on biphenyl moiety may attribute to the antiviral activity 66 . Compound 60 with a diherdral angle predicted to be −80° to −90°, possessed a highest potency against HIV in these series compounds.…”

1,2,3‐Triazole hybrids with anti‐HIV‐1 activity

“…The anti‐HIV‐1 IIIB SAR of 1,2,3‐triazole–pyrimidine hybrids 18 (Figure 4; EC 50 : 13–73 nM, the MTT [3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide] method using MT‐4 cells) and 19 (EC 50 : 56–5,620 nM) demonstrated that the linker between 1,2,3‐triazole and phenyl ring impacted the activity greatly, and the relative contribution order was as follows: without linker > methylene > ethylene > acetamide; the electron‐withdrawing group at the phenyl ring could enhance the activity. [ 59 ] The structure–cytotoxicity relationship revealed that extension of the carbon spacer between 1,2,3‐triazole and phenyl ring increased the cytotoxicity toward mock‐infected cells, and 1,2,3‐triazole–pyrimidine hybrids without linker exhibited the lowest cytotoxicity. The 1,2,3‐triazole–pyrimidine hybrids 18a , b (EC 50 : 20 and 13 nM) were not only comparable to AZT (EC 50 : 12 nM) against HIV‐1 IIIB , but they were also nontoxic toward mock‐infected cells (CC 50 : >241 µM), and the TI values were >11,830.…”

Targeting dual tolerant regions of binding pocket: Discovery of novel morpholine-substituted diarylpyrimidines as potent HIV-1 NNRTIs with significantly improved water solubility

“…Water solubility was measured in phosphate buffer at three different pH conditions. The compound was initially weighed in three orders of magnitude, namely approximately 0.01 mg, 0.1 mg and 1 mg, and then it was dissolved in the phosphate buffer of the same pH value until the solution was clear [43]. The average value of water solubility was calculated from the weight of the compound and the volume of the solution.…”