Novel Non-Nucleoside Inhibitors of Human Immunodeficiency Virus Type 1 Reverse Transcriptase. 6. 2-Indol-3-yl- and 2-Azaindol-3-yl- dipyridodiazepinones

Kelly, Terence A.; McNeil, Daniel W.; Rose, Janice; David, Eva; Shih, Cheng-Kon; Grob, Peter M.

doi:10.1021/jm960837y

Cited by 48 publications

(17 citation statements)

References 17 publications

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“…7). Stille coupling64 of 12 with N -Boc-3-(tributylstannyl)indole 33 65 followed by deprotection of Boc66 provided a fully functionalized precursor 34 (66% overall yield), which underwent a Ti(III)-catalysed radical cyclization under the same conditions as above to give decalin 35 as a single diastereomer in 60% yield39. In the presence of Pd(OAc) 2 and p -benzoquinone at 50 °C (refs 28, 29), 35 was converted to carbazole 21 in 81% yield, presumably through the devised oxidative Heck/aromatization sequence.…”

Section: Resultsmentioning

confidence: 99%

Total synthesis and antiviral activity of indolosesquiterpenoids from the xiamycin and oridamycin families

Meng

et al. 2015

Nat Commun

131

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Indolosesquiterpenoids are a growing class of natural products that exhibit a wide range of biological activities. Here, we report the total syntheses of xiamycin A and oridamycins A and B, indolosesquiterpenoids isolated from Streptomyces. Two parallel strategies were exploited to forge the carbazole core: 6π-electrocyclization/aromatization and indole C2–H bond activation/Heck annulation. The construction of their trans-decalin motifs relied on two diastereochemically complementary radical cyclization reactions mediated by Ti(III) and Mn(III), respectively. The C23 hydroxyl of oridamycin B was introduced by an sp3 C–H bond oxidation at a late stage. On the basis of the chemistry developed, the dimeric congener dixiamycin C has been synthesized for the first time. Evaluation of the antiviral activity of these compounds revealed that xiamycin A is a potent agent against herpes simplex virus–1 (HSV-1) in vitro.

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Section: Resultsmentioning

confidence: 99%

Total synthesis and antiviral activity of indolosesquiterpenoids from the xiamycin and oridamycin families

Meng

et al. 2015

Nat Commun

131

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“…Indoles substituted at C-3 [71,72] and their aza analogues [73] are known to exhibit remarkable biological activities. Particularly in the case of azaindoles, their ability to bind to the hinge region of kinases renders them promising structural motifs for kinase inhibition studies [74][75][76][77].…”

Section: Methodsmentioning

confidence: 99%

Sequentially Palladium-Catalyzed Processes in One-Pot Syntheses of Heterocycles

Lessing

Müller

2015

Applied Sciences

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Sequentially Pd-catalyzed processes are excellent entries to heterocycle synthesis. The broad mechanistic variety combined with often very mild reaction conditions allow the concatenation of elementary organic and organometallic steps to novel sequences in the sense of one-pot domino and multicomponent reactions. Given the numerous opportunities of alkyne coordination and their Pd-mediated transformations, alkynylation and carbometallation play a key role, both for purely organometallic sequences as well as in those processes that are intercepted by cyclocondensation. Pd-catalyzed aminations also find more and more entry into novel heterocycle syntheses based upon this theme.

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“…Ethyl 1-[(2-amino-5-chlorophenyl)sulfonyl]-1H-indole-2-carboxylate (25) and its 5-chloro derivative 27 were synthesized by phase transfer reaction [102] of the corresponding indole-2-carboxylic esters with 5-chloro-2-nitrobenzenesulfonyl chloride [103] in the presence of potassium tertbutoxide and 18-crown-6 in tetrahydrofuran at roomtemperature, followed by reduction of the nitro group (24,26) to amino (25,27) with iron powder by heating at 60 °C in glacial acetic acid. (Scheme 1).…”

Section: Synthesis Of Ias Derivativesmentioning

confidence: 99%

“…NNRTI agents have been recently widely reviewed [15][16][17][18][19][20][21]. Representative NNRTIs classes are dipyridodiazepinones [22][23][24][25][26][27][28], 4,5,6,7-tetrahydro-5-methylimidazo [4, 5, 1-jk] [1,4]benzodiazepin -2 (1H) -ones (TIBOs) [29][30][31][32], phenylethylthiazolylthioureas (PETTs) [33][34][35][36][37][38][39][40][41][42][43], bis(heteroaryl)piperazines (BHAPs) [44][45][46][47], quinazolinones [48][49][50][51][52][53][54][55][56][57], oxathiin carboxanilides [58][59][60][61]…”

Section: Introductionmentioning

confidence: 99%

Indolyl Aryl Sulfones (IASs): Development of Highly Potent NNRTIs Active Against wt-HIV-1 and Clinically Relevant Drug Resistant Mutants

Silvestri¹,

Artico²

2005

CPD

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Indolyl aryl sulfones (IASs) are a potent class of NNRTIs developed from L-737,126, a lead agent discovered by Merck AG. IAS derivatives are endowed with inhibitory activities against wt HIV-1 in the low nanomolar concentration range. Introduction of two methyl groups at positions 3 and 5 of the phenyl ring of the aryl sulfonyl moiety furnished IAS derivatives such as 5-chloro- or 5-bromo-3-[(3,5-dimethylphenyl)sulfonyl]indole-2-carboxyamide, which showed very potent and selective anti-HIV-1 activity against some mutants carrying NNRTI resistant mutations at positions 103 and 181 of the reverse transcriptase. IAS derivatives bearing 2-hydroxyethylcarboxyamide or 2-hydroxyethylcarboxyhydrazide groups at position 2 of the indole nucleus were more active than L-737,126 against the K103N-Y181C double mutant. A great improvement of antiviral activity against wt HIV-1 and resistant mutants was obtained by coupling 1-3 simple amino acids, such as glycine and alanine, in sequence, with the 3-[(3,5-dimethylphenyl)sulfonyl]-1H-indole-2-carbonyl moiety. The transformation of the chain terminus into amide or hydrazide, produced short peptides with high selectivity and potent activity against wt HIV-1, and the viral mutants Y181C, K103N-Y181C and EFV(R). IAS having two halogen atoms at the indole showed potent inhibitory activity against the Y181C and the EFV(R) resistant mutant strains. In particular, the introduction of a fluorine atom at position 4 of the indole ring notably contributed to improve the antiviral activities against both wt and the related resistant mutants. 5-Nitro-IASs were highly active against wt HIV-1 and exhibited low cytotoxicity. Experimental data highlighted the class IAS derivatives as promising candidates for clinical trials.

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Novel Non-Nucleoside Inhibitors of Human Immunodeficiency Virus Type 1 Reverse Transcriptase. 6. 2-Indol-3-yl- and 2-Azaindol-3-yl- dipyridodiazepinones

Abstract: Modification of the non-nucleoside inhibitor of HIV-1 reverse transcriptase nevirapine (Viramune) by incorporation of a 2-indolyl substituent confers activity against several mutant forms of the enzyme.

Cited by 48 publications

References 17 publications

Total synthesis and antiviral activity of indolosesquiterpenoids from the xiamycin and oridamycin families

Total synthesis and antiviral activity of indolosesquiterpenoids from the xiamycin and oridamycin families

Sequentially Palladium-Catalyzed Processes in One-Pot Syntheses of Heterocycles

Indolyl Aryl Sulfones (IASs): Development of Highly Potent NNRTIs Active Against wt-HIV-1 and Clinically Relevant Drug Resistant Mutants

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