Acquired Immunodeficiency Syndrome (AIDS) is a lethal infection caused by a retrovirus, the human immunodeficiency virus (HIV). Currently employed anti-AIDS drugs are classified into three main families, the nucleoside reverse transcriptase inhibitors (NRTIs), the non-nucleoside reverse transcriptase inhibitors (NNRTIs), and the protease inhibitors (PIs). NNRTIs received great attention because of their HIV-1 selectivity, low toxicity and favourable pharmacokinetic properties. Nevertheless first generation of NNRTI agents suffered from a rapid loss of activity following the emergence of single amino acids mutations in the Reverse Transcriptase (RT). Due to this reason they were not useful as standard components of the highly active antiretroviral therapy (HAART) of AIDS. Second generation NNRTIs, such as efavirenz, were active against a broad panel of mutant resistant strains and proved to be effective substitutes of PIs in HAART schedules. Therefore, there is still a need for second generation NNRTIs for clinical use. Three NNRTIs are commercially available: nevirapine (Viramune®, 1), delavirdine (Rescriptor®, 2) and efavirenz (Sustiva®, 3), but a large number of NNRTIs have been identified. Among them pyrrolobenzothiazepines (PBTDs, 4), pyrryl aryl sulfones (PASs, 5), 1-[2-(diarylmethoxy)ethyl]-2-methyl-5-nitroimidazoles (DAMNIs, 6) and acylamino pyrryl aryl sulfones (APASs, 7) were discovered in our department (Chart 1). Prolonged HAART treatments lead to the emergence of drug resistant mutant strains. Thus, searches for novel anti-AIDS agents, active also against viral mutants, need. L-737,126 (8)1 is a sulfonyl indole-2-carboxyamide, discovered by Merck Laboratories, which showed anti-HIV-1 activity at nanomolar concentrations, but it appeared poorly active against HIV-1 strains carrying clinically relevant mutations. We focused our attention on the synthesis of novel indolyl aryl sulfones (IASs) active on viral mutants variants of clinical relevance. Structure Activity Relationship (SAR) studies led us to introduce two methyl groups at positions 3 and 5 of L,737-126 benzenesulfonyl moiety. The most interesting compound of the IAS series (compound 9) showed selectivity and activity at nanomolar concentrations on WT, Y181C, K103N-Y181C and K103-V179D-P225H mutant strains.2 The modulation of the 2-carboxyamide chain led to synthesize 5-chloro-3-arylsulfonyl-1H-indole-2-carboxyamides bearing in sequence one, two or three aminoacids units. Transformation of chain end into amide or hydrazide produced IAS derivatives with potent and selective activity against HIV-1 WT and NNRTI resistant mutants. The glycinyl-glycine carboxyamide was active against the WT strain at EC50 = 0.7 nM; the alanine carboxyamide resulted the most active compound against the double (K103N-Y181C) and triple (K103R-V179D-P225H) mutants. IAS derivatives with N-(2-heterocycloethyl)- or N-(2-arylethyl)-2-carboxyamide portion were found also highly selective and active at nanomolar concentration against some resistant mutants (Chart 2). The interesting biological profile displayed by the new indolyl aryl sulfones encourage us in further investigations. Synthesis of IASs. Ethyl or methyl 3-arylthio-5-chloro-1H-indole-2-carboxylates were prepared by reaction of proper N-(arylthio)succinimide with ethyl or methyl 5-chloro-1H-indole-2-carboxylates in the presence of boron trifluoride diethyl etherate. Oxidation of 3-arylthio-1H-indole-2-carboxylates to the related sulfones was performed with 3-chloroperoxybenzoic acid. The hydrolysis of the 3-arylsulfonyl-5-chloro-1H-indole-2-carboxylates with lithium hydroxide furnished the corresponding acids, which were condensed with ethyl or methyl esters of D,L-aminoacids in the presence of BOP and triethylamine. Dipeptide or tripeptide derivatives were prepared under same reaction conditions. The corresponding amides and hydrazides were synthesized reacting the esters with ammonium hydroxide or hydrazine respectively. References (1) Williams, T. M.; Ciccarone, T. M.; Mactough, S. C. Rooney, C. S.; Balani, S. K.; Condra, J. H.; Emini, E. A.; Goldman, M. E.; Greenlee, W. J.; Kauffman, L. R.; O’ Brien, J. A.; Sardana, V. V.; Schleif, W. A.; Theoharides, A. D.; Anderson, P. S. 5-Chloro-3-(phenylsulfonyl)indole-2-carboxamide: a novel non-nucleoside reverse transcriptase inhibitor. J. Med. Chem. 1993, 36, 1291-1294. (2) Silvestri, R.; De Martino, G.; La Regina, G.; Artico, M.; Massa, S.; Vargiu, L.; Mura, M.; Loi, A. G.; Marceddu, T.; La Colla, P. Novel indolyl aryl sulfones active against HIV-1 carrying NNRTI resistance mutations: synthesis and SAR studies. J. Med. Chem. 2003, 46, 2482-2493.
Novel indolyl aryl sulfones (IASs) highly active in vitro against HIV-1 WT and variants carrying NNRTI resistance mutations / LA REGINA, Giuseppe. - (2004), pp. 85-85. (Intervento presentato al convegno European School of Medicinal Chemistry tenutosi a Urbino).
Novel indolyl aryl sulfones (IASs) highly active in vitro against HIV-1 WT and variants carrying NNRTI resistance mutations
LA REGINA, GIUSEPPE
2004
Abstract
Acquired Immunodeficiency Syndrome (AIDS) is a lethal infection caused by a retrovirus, the human immunodeficiency virus (HIV). Currently employed anti-AIDS drugs are classified into three main families, the nucleoside reverse transcriptase inhibitors (NRTIs), the non-nucleoside reverse transcriptase inhibitors (NNRTIs), and the protease inhibitors (PIs). NNRTIs received great attention because of their HIV-1 selectivity, low toxicity and favourable pharmacokinetic properties. Nevertheless first generation of NNRTI agents suffered from a rapid loss of activity following the emergence of single amino acids mutations in the Reverse Transcriptase (RT). Due to this reason they were not useful as standard components of the highly active antiretroviral therapy (HAART) of AIDS. Second generation NNRTIs, such as efavirenz, were active against a broad panel of mutant resistant strains and proved to be effective substitutes of PIs in HAART schedules. Therefore, there is still a need for second generation NNRTIs for clinical use. Three NNRTIs are commercially available: nevirapine (Viramune®, 1), delavirdine (Rescriptor®, 2) and efavirenz (Sustiva®, 3), but a large number of NNRTIs have been identified. Among them pyrrolobenzothiazepines (PBTDs, 4), pyrryl aryl sulfones (PASs, 5), 1-[2-(diarylmethoxy)ethyl]-2-methyl-5-nitroimidazoles (DAMNIs, 6) and acylamino pyrryl aryl sulfones (APASs, 7) were discovered in our department (Chart 1). Prolonged HAART treatments lead to the emergence of drug resistant mutant strains. Thus, searches for novel anti-AIDS agents, active also against viral mutants, need. L-737,126 (8)1 is a sulfonyl indole-2-carboxyamide, discovered by Merck Laboratories, which showed anti-HIV-1 activity at nanomolar concentrations, but it appeared poorly active against HIV-1 strains carrying clinically relevant mutations. We focused our attention on the synthesis of novel indolyl aryl sulfones (IASs) active on viral mutants variants of clinical relevance. Structure Activity Relationship (SAR) studies led us to introduce two methyl groups at positions 3 and 5 of L,737-126 benzenesulfonyl moiety. The most interesting compound of the IAS series (compound 9) showed selectivity and activity at nanomolar concentrations on WT, Y181C, K103N-Y181C and K103-V179D-P225H mutant strains.2 The modulation of the 2-carboxyamide chain led to synthesize 5-chloro-3-arylsulfonyl-1H-indole-2-carboxyamides bearing in sequence one, two or three aminoacids units. Transformation of chain end into amide or hydrazide produced IAS derivatives with potent and selective activity against HIV-1 WT and NNRTI resistant mutants. The glycinyl-glycine carboxyamide was active against the WT strain at EC50 = 0.7 nM; the alanine carboxyamide resulted the most active compound against the double (K103N-Y181C) and triple (K103R-V179D-P225H) mutants. IAS derivatives with N-(2-heterocycloethyl)- or N-(2-arylethyl)-2-carboxyamide portion were found also highly selective and active at nanomolar concentration against some resistant mutants (Chart 2). The interesting biological profile displayed by the new indolyl aryl sulfones encourage us in further investigations. Synthesis of IASs. Ethyl or methyl 3-arylthio-5-chloro-1H-indole-2-carboxylates were prepared by reaction of proper N-(arylthio)succinimide with ethyl or methyl 5-chloro-1H-indole-2-carboxylates in the presence of boron trifluoride diethyl etherate. Oxidation of 3-arylthio-1H-indole-2-carboxylates to the related sulfones was performed with 3-chloroperoxybenzoic acid. The hydrolysis of the 3-arylsulfonyl-5-chloro-1H-indole-2-carboxylates with lithium hydroxide furnished the corresponding acids, which were condensed with ethyl or methyl esters of D,L-aminoacids in the presence of BOP and triethylamine. Dipeptide or tripeptide derivatives were prepared under same reaction conditions. The corresponding amides and hydrazides were synthesized reacting the esters with ammonium hydroxide or hydrazine respectively. References (1) Williams, T. M.; Ciccarone, T. M.; Mactough, S. C. Rooney, C. S.; Balani, S. K.; Condra, J. H.; Emini, E. A.; Goldman, M. E.; Greenlee, W. J.; Kauffman, L. R.; O’ Brien, J. A.; Sardana, V. V.; Schleif, W. A.; Theoharides, A. D.; Anderson, P. S. 5-Chloro-3-(phenylsulfonyl)indole-2-carboxamide: a novel non-nucleoside reverse transcriptase inhibitor. J. Med. Chem. 1993, 36, 1291-1294. (2) Silvestri, R.; De Martino, G.; La Regina, G.; Artico, M.; Massa, S.; Vargiu, L.; Mura, M.; Loi, A. G.; Marceddu, T.; La Colla, P. Novel indolyl aryl sulfones active against HIV-1 carrying NNRTI resistance mutations: synthesis and SAR studies. J. Med. Chem. 2003, 46, 2482-2493.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
