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Through a structure-guided core-refining approach, a series of novel imidazo[1,2- a ]pyrazine derivatives were designed, synthesized and evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Biological results of antiviral assay in MT-4 cell cultures showed that 12 target compounds displayed moderate activities against wild-type (wt) HIV-1 strain (III B ) with EC 50 values ranging from 0.26 μM to 19 μM. Among them, 4a and 5a were found to be the two most active analogues possessing EC 50 values of 0.26 μM and 0.32 μM respectively, comparable to delavirdine (DLV, EC 50 = 0.54 μM) and nevirapine (NVP, EC 50 = 0.31 μM) in a cell-based assay. Additionally, 9 compounds showed RT inhibitory activity superior to that of NVP. Moreover, some predicted drug-like properties of representative compounds 4a and 5a , as well as the structure-activity relationship (SAR) analysis were discussed in detail. The binding mode of compound 4a was investigated by molecular simulation studies. [ABSTRACT FROM AUTHOR]

In our arduous efforts to develop new potent HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs), novel piperidine-linked [1,2,4]triazolo[1,5- a ]pyrimidine derivatives were designed, synthesized and evaluated for their antiviral activities in MT-4 cell cultures. Biological results showed that all of the title compounds displayed moderate to excellent activities against wild-type (wt) HIV-1 strain (III B ) with EC 50 values ranging from 8.1 nM to 2284 nM in a cell-based assay. Among them, the most promising analog 7d possessed an EC 50 value of 8.1 nM against wt HIV-1, which was much more potent than the reference drugs DDI, 3 TC, NVP and DLV. Additionally, 7d demonstrated weak activity against the double mutant HIV-1 strain (K103N + Y181C), and was more efficient than NVP in a RT inhibition assay. Besides, some measured and calculated physicochemical properties of 7d , like log P and water solubility, as well as the structure–activity relationships (SARs) analysis have been discussed in detail. Furthermore, the binding mode of the active compound 7d was rationalized by molecular simulation studies. [ABSTRACT FROM AUTHOR]

Abstract: A probable NRTI molecule, viz. 3′-N,N-dimethylamino-2′,3′-dideoxythymidine (4) and its 5′-O-carboxyl ester prodrugs – 5′-(N-α-BOC-l-phenylalanyl)-3′-N,N-dimethylamino-2′,3′-dideoxythymidine (5), 5′-l-phenylalanyl-3′-N,N-dimethylamino-2′,3′-dideoxythymidine (6) and 5′-decanoyl-3′-N,N-dimethylamino-2′,3′-dideoxythymidine (7) have been synthesized and screened against HIV, HSV-1 and 2, parainfluenza-3, vesicular stomatitis and several other viruses. The compound 6 showed good antiviral activity with EC50 value 0.03μM (SI=8) against VSV in Hela and HEL cell lines. However, the lead compound 4 and its derivatives 5, 6 and 7 showed no remarkable activity against HIV-1 and other viruses. Molecular docking studies with HIV-1 RT using DS 2.5 and pymol softwares have shown marked differences in the interaction patterns between the lead compound 4 and AZT. [ABSTRACT FROM AUTHOR]

Abstract: For the activity values against HIV-1 RT wild-type and mutant strains (L100I, Y181C and Y188N) of 34 diarylpyrimidines (DAPYs) taken from literature, multiple linear regression analysis and the crossvalidation of Leave-One-Out method are carried out against the activity values with the hydrophobicity index log P, the modified steric parameter L Y, the Muliken charge of nitrogen atom on the right wing N C and the indicator index I for the substituents R3′ and R1 on the left wing, and four good QSAR models are established: R =0.8211(N =34), R =0.8599 (N =33), R =0.8711(N =30) and R =0.9079 (N =29) for the cases of wild type, and mutant strain forms L100I, Y181C and Y188N, respectively. Additionally, the results indicate that log P plays a vital role in the prediction of the activity of DAPYs, and the cyano group on the left wing is important for inhibiting the mutant forms L100I and Y188N. [Copyright &y& Elsevier]

This paper reports the synthesis and antiviral evaluation of a series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine the peculiar structural features of diarylpyrimidine derivatives (DAPYs) and benzophenone derivatives (BPs). The DAPY derivatives bearing benzoyl or alkoxyl substitutes on the A-ring showed the inhibitory activity against wild-type HIV-1 at the cellular level within the range of EC50 values from micromolar to nanomolar. Among these compounds, 1u exhibited the most potent anti-HIV-1 activity (EC50 = 0.06 ± 0.01 μM, SI > 6260), which were about 1.8-fold more active than nevirapine (NVP) and delavirdine (DLV). In addition, the binding modes with HIV-1 RT and the preliminary SAR studies of these derivatives were also considered for further investigation., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)