Pyrrolobenzothiazepinones and Pyrrolobenzoxazepinones: Novel and Specific Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors with Antiviral Activity (original) (raw)
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Journal of Medicinal Chemistry, 1995
The major cause of viral resistance to the potent human immunodeficiency virus type 1 reverse transcriptase (RT) inhibitor nevirapine is the mutation substituting cysteine for tyrosine-181 in RT (Y181C RT). An evaluation, against Y181C RT, of previously described analogs of nevirapine revealed that the 2-chlorodipyridodiazepinone 16 is an effective inhibitor of this mutant enzyme. The detailed examination of the structure-activity relationship of 2-substituted dipyridodiazepinones presented below shows that combined activity against the wildtype and Y181C enzymes is achieved with aryl substituents at the 2-position of the tricyclic ring system. In addition, the substitution pattern at C-4, N-5, and N-11 of the dipyridodiazepinone ring system optimum for inhibition of both wild-type and Y181C RT is no longer the 4-methyl-11-cyclopropyl substitution preferred against the wild-type enzyme but rather the 5-methyl-11-ethyl (or 11-cyclopropyl) pattern. The more potent 2-substituted dipyridodiazepinones were evaluated against mutant RT enzymes (LlOOI RT, K103N RT, P236L RT, and E138K RT) that confer resistance to other non-nucleoside RT inhibitors, and compounds 42, 62, and 67, with pyrrolyl, aminophenyl, and aminopyridyl substituents, respectively, at the 2-position, were found to be effective inhibitors of these mutant enzymes also.
Novel Non-nucleoside Inhibitors of Human Immunodeficiency Virus Type 1 (HIV-1)
Journal of Medicinal Chemistry
The major cause of viral resistance to the potent human immunodeficiency virus type 1 reverse transcriptase (RT) inhibitor nevirapine is the mutation substituting cysteine for tyrosine-181 in RT (Y181C RT). An evaluation, against Y181C RT, of previously described analogs of nevirapine revealed that the 2-chlorodipyridodiazepinone 16 is an effective inhibitor of this mutant enzyme. The detailed examination of the structure-activity relationship of 2-substituted dipyridodiazepinones presented below shows that combined activity against the wildtype and Y181C enzymes is achieved with aryl substituents at the 2-position of the tricyclic ring system. In addition, the substitution pattern at C-4, N-5, and N-11 of the dipyridodiazepinone ring system optimum for inhibition of both wild-type and Y181C RT is no longer the 4-methyl-11-cyclopropyl substitution preferred against the wild-type enzyme but rather the 5-methyl-11-ethyl (or 11-cyclopropyl) pattern. The more potent 2-substituted dipyridodiazepinones were evaluated against mutant RT enzymes (LlOOI RT, K103N RT, P236L RT, and E138K RT) that confer resistance to other non-nucleoside RT inhibitors, and compounds 42, 62, and 67, with pyrrolyl, aminophenyl, and aminopyridyl substituents, respectively, at the 2-position, were found to be effective inhibitors of these mutant enzymes also.
Synthesis of N-Hydroxypyrazinones as Potential HIV Inhibitors
2015
De C3-functionalisatie van N-hydroxypyrazinonen werd in deze thesis grondig bestudeerd. Dit leidde tot de succesvolle synthese van een bibliotheek met drie nieuwe klassen van verbindingen, waaronder 3-alkyl-, 3-carboxamide-, en 3-ureidoalkyl-1-hydroxypyrazinonen. Met behulp van flow chemie en katalytische transfer-hydrogenering werd een reproduceerbare methodologie ontwikkeld voor de selectieve debenzylering van O-benzyl-beschermde N-hydroxypyrazinonen. Deze methodologie kan opgeschaald worden van milligramschaal naar gramschaal met behulp van gepaste flowinstrumenten. Talrijke N-hydroxypyrazinonen werden bereid met het oog op HIV inhibitie activiteit. De resultaten verkregen uit de in vitro biologische evaluatie van HIV-1 en HIV-2 replicatie in humane T-lymfocytcellen (door middel van een MTT-test) hebben echter aantoond dat geen enkele van de verbindingen inhibitorische activiteit vertonen. Een aantal verbindingen daarentegen vertoont echter wel inhibitie activiteit in een HIV-1 reverse transcriptase polymerase test. xi List of Abbreviations and Symbols δ Chemical shift in parts per million downfield from tetramethylsilane Ø Mole fraction of a solvent in an aqueous solution ABTS 2,2'-Azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) Ac Acetyl ACN Acetonitrile AIDS Acquired immune deficiency syndrome All Allyl AMD3100 1,1′-[1,4-Phenylenebis(methylene)]bis-1,4,8,11-tetraazacyclotetradecane API-ES Atmospheric pressure ionization electrospray aq Aqueous Ar Aryl ART Antiretroviral therapy Asp Aspartic acid (D) AZT Azidothymidine B3LYP 3-Parameter hybrid Becke exchange/Lee-Yang-Parr correlation functional brd Broad doublet (in NMR spectrometry) Bn Benzyl Boc tert-Butoxycarbonyl BPR Backpressure regulator brs Broad singlet (in NMR spectrometry) calcd Calculated Cbz Carbobenzyloxy CCID50 Cell culture infectious dose CCR5 Chemokine receptor type 5 CD4 Cluster of differentiation 4 (a glycoprotein on surface of immune cells) CDCl3 Deuterated chloroform CD3OD Deuterated methanol Compd. Compound CXCR4 Chemokine receptor type 4 Cy Cyclohexyl CYP3A4 Enzyme responsible for oxidizing foreign organic molecules in metabolism
Journal of Medicinal Chemistry, 1995
The major cause of viral resistance to the potent human immunodeficiency virus type 1 reverse transcriptase (RT) inhibitor nevirapine is the mutation substituting cysteine for tyrosine-181 in RT (Y181C RT). An evaluation, against Y181C RT, of previously described analogs of nevirapine revealed that the 2-chlorodipyridodiazepinone 16 is an effective inhibitor of this mutant enzyme. The detailed examination of the structure-activity relationship of 2-substituted dipyridodiazepinones presented below shows that combined activity against the wildtype and Y181C enzymes is achieved with aryl substituents at the 2-position of the tricyclic ring system. In addition, the substitution pattern at C-4, N-5, and N-11 of the dipyridodiazepinone ring system optimum for inhibition of both wild-type and Y181C RT is no longer the 4-methyl-11-cyclopropyl substitution preferred against the wild-type enzyme but rather the 5-methyl-11-ethyl (or 11-cyclopropyl) pattern. The more potent 2-substituted dipyridodiazepinones were evaluated against mutant RT enzymes (LlOOI RT, K103N RT, P236L RT, and E138K RT) that confer resistance to other non-nucleoside RT inhibitors, and compounds 42, 62, and 67, with pyrrolyl, aminophenyl, and aminopyridyl substituents, respectively, at the 2-position, were found to be effective inhibitors of these mutant enzymes also.
Journal of Medicinal Chemistry, 2005
A series of novel 8-substituted dipyridodiazepinone-based inhibitors were investigated for their antiviral activity against wild type human immunodeficiency virus (HIV-1) and the clinically prevalent K103N/Y181C mutant virus. Our efforts have resulted in a series of benzoic acid analogues that are potent inhibitors of HIV-1 replication against a panel of HIV-1 strains resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Furthermore, the combination of good antiviral potency, a broad spectrum of activity, and an excellent pharmacokinetic profile provides strong justification for the further development of compound 7 as a potential treatment for wild type and NNRTI-resistant HIV-1 infection.
Synthesis of Substituted Benzoxazepinones as Potential Anti-retroviral Drug Analogues
The syntheses of 8-nitro-1,2,3,3a-tetrahydropyrrolo(1,2-a)[4,1]benzoxazepin-6-one 10 and 2-hydroxy-8-nitro-1,2,3,3a-tetrahydropyrrolo(1,2-a)[4,1]benzoxazepine-4,6-dione 11 were achieved via a two-step reaction pathway; condensation followed by dehydration. 2-Chloro-5-nitrobenzoic acid 5 was separately condensed with L-pyrrolidine-2-methanol (L-prolinol) 6 and 4-hydroxy-L-pyrrolidine-2-carboxylic acid (4-hydroxyl-L-proline) 7 to give the condensation products; N-(2’-carboxy-4’-nitrophenyl)-L-prolinol 8 and N-(2’-carboxy-4’-nitrophenyl)-4-hydroxy-L-proline 9, respectively – precursors to the target molecules 10 and 11. N-(2’-carboxy-4’-nitrophenyl)-L-pyrrolidine-2-methanol 8 afforded 8-nitro-1,2,3,3a-tetrahydro pyrrolo(1,2-a)[4,1]benzoxazepin-6-one 10 on dehydration with trifluoroacetic acid while N-(2’-carboxy-4’-nitrophenyl)-4-hydroxy-L-pyrrolidine-2-carboxylic acid 9 in refluxing acetic anhydride gave 2-hydroxy-8-nitro-1,2,3,3a-tetrahydropyrrolo(1,2-a)[4,1] benzoxazepine-4,6-dione 11, both in good yields.
European journal of medicinal chemistry, 2017
In this report, we present a new benzoxazole derivative endowed with inhibitory activity against the HIV-1 nucleocapsid protein (NC). NC is a 55-residue basic protein with nucleic acid chaperone properties, which has emerged as a novel and potential pharmacological target against HIV-1. In the pursuit of novel NC-inhibitor chemotypes, we performed virtual screening and in vitro biological evaluation of a large library of chemical entities. We found that compounds sharing a benzoxazolinone moiety displayed putative inhibitory properties, which we further investigated by considering a series of chemical analogues. This approach provided valuable information on the structure-activity relationships of these compounds and, in the process, demonstrated that their anti-NC activity could be finely tuned by the addition of specific substituents to the initial benzoxazolinone scaffold. This study represents the starting point for the possible development of a new class of antiretroviral agent...
Bioorganic & Medicinal Chemistry, 2011
A series of (±)-benzhydrol derivatives featuring the essential sulfonamide group at the para position on the C-ring were synthesized and evaluated for the potential anti-HIV activity in C8166 cells. Most of these analogues demonstrated low concentration inhibitory activity with EC 50 values less than 1 lM against the wild-type HIV-1. In particular, compound 7h was identified as the highest active inhibitor of wildtype HIV-1 with an EC 50 value of 0.12 lM and selectivity index value of 312.73. Furthermore, some of them also exhibited moderate activity against the double mutant strain A 17 (K103N + Y181C) with EC 50 values lower than 5 lM. In addition, the binding modes with RT and the preliminary structureactivity relationships of these derivatives were also explored for further chemical modifications.
Discovery and optimization of pyridazinone non-nucleoside inhibitors of HIV-1 reverse transcriptase
Bioorganic & Medicinal Chemistry Letters, 2008
A series of benzyl pyridazinones were evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Several members of this series showed good activity against the wild-type virus and NNRTIresistant viruses. The binding of inhibitor 5a to HIV-RT was analyzed by surface plasmon resonance spectroscopy. Pharmacokinetic studies of 5a in rat and dog demonstrated that this compound has good oral bioavailability in animal species. The crystal structure of a complex between HIV-RT and inhibitor 4c is also described.