Discovery and optimization of pyridazinone non-nucleoside inhibitors of HIV-1 reverse transcriptase

Sweeney, Zachary K.; Dunn, James P.; Liu, Yu; Heilek, Gabrielle; Dunten, Pete; Elworthy, Todd R.; Han, Xiaochun; Harris, S.F.; Hirschfeld, Donald R.; Hogg, J. Heather; Huber, Walter; Kaiser, Ann C.; Kertesz, Denis J.; Kim, Woongki; Mirzadegan, Taraneh; Roepel, Michael G.; Saitō, Yoshio; Silva, Tania M.P.C.; Swallow, Steven; Tracy, Jahari Laurant; Villaseñor, Armando G.; Vora, Harit; Zhou, Amy S.; Klumpp, Klaus

doi:10.1016/j.bmcl.2008.06.072

Cited by 39 publications

(20 citation statements)

References 15 publications

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“…Unlike the reported DAPY derivatives,13-15 the new analogs designed in this study (Figure 2) have a central benzene ring rather than the pyrimidine in DAPY compounds. The new compounds also retain two phenyl rings in the eastern and western wings, but have different para -substituents from the DAPY compounds.…”

Section: Designmentioning

confidence: 83%

Diarylaniline Derivatives as a Distinct Class of HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors

Qin¹,

Jiang²,

Liang

et al. 2010

J. Med. Chem.

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By using structure-based drug design and isosteric replacement, diarylaniline and 1,5-diarylbenzene-1,2-diamine derivatives were synthesized and evaluated against wild type HIV-1 and drug-resistant viral strains, resulting in the discovery of diarylaniline derivatives as a distinct class of next-generation HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) agents. The most promising compound 37 showed significant EC 50 values of 0.003-0.032 μM against HIV-1 wild-type strains and of 0.005-0.604 μM against several drug-resistant strains. Current results also revealed important structure-activity relationship (SAR) conclusions for diarylanilines and strongly support our hypothesis that an NH 2 group on the central benzene ring ortho to the aniline moiety is crucial for interaction with K101 of the NNRTI binding site in HIV-1 RT, likely by forming H-bonds with K101. Furthermore, molecular modeling studies with molecular mechanism/general born surface area (MM/GBSA) technology demonstrated the rationality of our hypothesis.

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Section: Designmentioning

confidence: 83%

Diarylaniline Derivatives as a Distinct Class of HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors

Qin¹,

Jiang²,

Liang

et al. 2010

J. Med. Chem.

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“…50 is reported to have anti-HIV activities in cell assays of 4.7, 13.8, and 141 nM for the WT, Y181C, and K103N/Y181C variants, 33 while the corresponding values for 51 are 1, 1, and 4 nM. 34a Thus, these compounds are less potent towards wild-type HIV-1 than 42 or 44 , while 51 has the best results for the mutant strains.…”

Section: Resultsmentioning

confidence: 99%

“…33,34 The illustrated 50 and 51 appear to be the most promising compounds from these efforts. They are clearly far more similar to each other than to 42 - 44 .…”

Section: Resultsmentioning

confidence: 99%

Computationally-Guided Optimization of a Docking Hit to Yield Catechol Diethers as Potent Anti-HIV Agents

et al. 2011

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A 5-μM docking hit has been optimized to an extraordinarily potent (55 pM) non-nucleoside inhibitor of HIV reverse transcriptase. Use of free energy perturbation (FEP) calculations to predict relative free energies of binding aided the optimizations by identifying optimal substitution patterns for phenyl rings and a linker. The most potent resultant catechol diethers feature terminal uracil and cyanovinylphenyl groups. A halogen bond with Pro95 likely contributes to the extreme potency of compound 42. In addition, several examples are provided illustrating failures of attempted grafting of a substructure from a very active compound onto a seemingly related scaffold to improve its activity.

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“…In addition, the 1 H NMR spectra of compounds 2a-e revealed the absence of proton bands of the methylene moiety. The existence of compound 2c was supported by its 1 Pyrano [2,3- …”

Section: Chemistrymentioning

confidence: 99%

New pyrano[2,3-c]pyridazine derivatives with antimicrobial activity synthesized using piperidine as the organocatalyst

Kandile

Zaky

2014

Journal of Enzyme Inhibition and Medicinal Chemistry

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A simple and efficient method for the synthesis of highly diverse pyrano [2,3-c]pyridazines was achieved by a one pot multicomponent reaction using piperidine as the organocatalyst. The synthesis of a series of heterocyclic derivatives with varying functionality (e.g. thiazine, tetrazole and pyrimidine) incorporating the pyrano[2,3-c]pyridazine moiety were achieved via reaction of 2a-e with different reagents. The structures of the synthesized derivatives were elucidated by FTIR, MS, 1 H and 13 C NMR spectroscopy. A number of the newly synthesized targeted compounds 2b-e, 3a-c and 4a-c were evaluated for their in vitro antibacterial activity and were compared with chloramphenicol and nystatin as broad spectrum reference standard antibiotics. Tests were carried out against Staphylococcus aureus (MTCC3160) and Enterococcusi fecalis as Gram-positive bacteria, and Escherichia coli (MTCC1652) and Klebsiella pneumonia as Gram-negative bacteria. Antifungal potential against Candida albicans, and Aspergillus albicans strains were also evaluated. The results revealed that compounds 3a and 3c showed strong significant activity relative to the reference against these bacterial and fungal strains.

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Discovery and optimization of pyridazinone non-nucleoside inhibitors of HIV-1 reverse transcriptase

Cited by 39 publications

References 15 publications

Diarylaniline Derivatives as a Distinct Class of HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors

Diarylaniline Derivatives as a Distinct Class of HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors

Computationally-Guided Optimization of a Docking Hit to Yield Catechol Diethers as Potent Anti-HIV Agents

New pyrano[2,3-c]pyridazine derivatives with antimicrobial activity synthesized using piperidine as the organocatalyst

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