Exploration of piperidine-4-yl-aminopyrimidines as HIV-1 reverse transcriptase inhibitors. N-Phenyl derivatives with broad potency against resistant mutant viruses

Abstract

Further investigation of the recently reported piperidine-4-yl-aminopyrimidine class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) has been carried out. Thus, preparation of a series of N-phenyl piperidine analogs resulted in the identification of 3-carboxamides as a particularly active series. Analogs such as 28 and 40 are very potent versus wild-type HIV-1 and a broad range of NNRTI-resistant mutant viruses. Synthesis, structure-activity relationship (SAR), clearance data, and crystallographic evidence for the binding motif are discussed.

QSAR models and scaffold-based analysis of non-nucleoside HIV RT inhibitors

“…Publicly available NNRTIs with a pyrimidine ring in their structure shown to possess anti-HIVRT activity were obtained from the ChemDB database [14] and published articles [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. To maintain homogeneity in the dataset, only molecules with reported IC 50 values (against HIV RT) were considered.…”

Thermochemical study of dichloromethylpyrimidine isomers

“…In the same table we also collect the literature experimental data of the standard molar enthalpies of formation in the gaseous phase, at T = 298.15 K [60][61][62][63]16,64]. The calculated reaction enthalpies for the reactions (8)- (14) and the estimates of the gas-phase standard molar enthalpies of formation, at T = 298.15 K, are presented in the supporting information, Table S6 for 2,4-dichloro-5-methylpyrimidine, Table S7 for 2,4-dichloro-6-methylpyrimidine, Table S8 for 4,6-dichloro-2-methylpyrimidine, Table S9 for 4,6-dichloro-5-methylpyrimidine, Table S10 for 2,5-dichloro-4-methylpyrimidine, Table S11 for 4,5-dichloro-2-methylpyrimidine and Table S12 for 4,5-dichloro-6-methylpyrimidine.…”

“…(Table 3), and the enthalpy of phase transition (Table 5). c Mean value for the working reactions (8)- (14) and standard deviation of the mean. d Difference between the experimental and computational values.…”

“…The computational gas-phase molar enthalpies of formation calculated for all the compounds considering the working reactions (8)- (14) are presented in Table 6 (mean value of all reactions considered). These are shown together with the experimental values for the chloromethylpyrimidines studied, obtained by combining the respective standard molar enthalpies of formation, in the crystalline phase (Table 4) and the enthalpies of phase transition (Table 5).…”

“…Pyrimidine derivatives containing amino and chloro substituents have been used recently in more directed clinical studies: the 5-amino-2,4-dichloropyrimidine has been employed in the synthesis of piperidine-4-yl-aminopyrimidine derivatives, which are HIV-1 reverse transcriptase inhibitors [14]. On the other hand, 2,4-dichloro-5-(2-chloroethyl)pyrimidine was evaluated for cytostatic activity against human malignant tumor cell lines: acute lymphoblastic leukemia, colon carcinoma, breast carcinoma and lung carcinoma [15].…”