Structure-based discovery of novel diarylpyrimidines as potent and selective Non-Nucleoside reverse transcriptase inhibitors: From CH(CN)-Biphenyl-Diarylpyrimidines to CNNH-Biphenyl-Diarylpyrimidines.

In order to enhance the anti-HIV-1 potency and selectivity of the previously reported compound 3 (EC = 27 nM, SI = 1361), a series of novel biphenyl-diarylpyrimidine derivatives were developed by employing structure-based drug design strategy. Among these derivatives, compound M44 demonstrated the most potent inhibitory activity against wild-type (WT) HIV-1 as well as five drug-resistant mutants (EC = 5-148 nM), which were 5-173 times more potent than that of 3 (EC = 27-9810 nM). Furthermore, this analogue exhibited approximately 11-fold lower cytotoxicity (CC = 54 μM) than that of etravirine and rilpivirine.

Like milk on the stove: Healthcare professionals navigating uncertainty when caring for families with 22q11DS.

Introduction: 22q11 deletion syndrome (22q11DS) results from a microdeletion on chromosome 22 and is the most common microdeletion disorder in humans, affecting 1 in 2148 live births. Clinical manifestations vary widely among individuals and across different life stages. Effective management requires the involvement of a specialized multidisciplinary team.

Does Ortho-Substitution Enhance Cytotoxic Potencies in a Series of 3,5-Bis(benzylidene)-4-piperidones?

A series of 3,5-benzylidene-4-piperidones, -, were prepared to evaluate the hypothesis that the placement of different groups in the ortho-location of the aryl rings led to compounds with greater cytotoxic potencies than structural analogs. The bioevaluation of - was undertaken using human Molt/4C8 and CEM cells as well as murine L1210 cells. Correlations were sought between the interplanar angles θ and θ and the cytotoxic potencies.

Discovery of novel fused-heterocycle-bearing diarypyrimidine derivatives as HIV-1 potent NNRTIs targeting tolerant region I for enhanced antiviral activity and resistance profile.

As an important part of anti-AIDS therapy, HIV-1 non-nucleoside reverse transcriptase inhibitors are plagued by resistance and toxicity issues. Taking our reported XJ-18b1 as lead compound, we designed a series of novel diarypyrimidine derivatives by employing a scaffold hopping strategy to discover potent NNRTIs with improved anti-resistance properties and drug-like profiles. The most active compound 3k exhibited prominent inhibitory activity against wild-type HIV-1 (EC = 0.

In memory of an exquisite medicinal chemist, Prof. Morris Robins.

Among the most prominent realizations of Morris J. Robins in the antiviral nucleoside chemistry are the synthesis of 8-substituted (methyl-, amino-, bromo-, iodo) derivatives of acyclovir, xylotubercidin as an inhibitor of herpes simplex virus (HSV) infections, the anti-HIV activity of the 2',3'-dideoxyriboside of 2,6-diaminopurine (ddDAPR) and the 3'-azido- and 3'-fluoro derivatives thereof (AzddDAPR and FddDAPR, respectively), the potentiating effect of ribavirin on the anti-HIV activity of 2',3'-dideoxyinosine (ddI) and ddDAPR, S-adenosylhomocysteine hydrolase (SAH) inhibitors principally active against vaccinia virus (VV) and vesicular stomatitis virus (VSV), and furo[2,3-d]pyrimidinone derivatives active against varicella-zoster virus (VZV).