New Carboxamides of the Thieno[3,2- b ]pyrrole Series
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New Carboxamides of the Thieno[3,2-b]pyrrole Series S. A. Torosyana, Z. F. Nuriakhmetovaa, F. A. Gimalovaa,*, and M. S. Miftakhova a
Ufa Institute of Chemistry, Ufa Federal Research Center, Russian Academy of Sciences, Ufa, 450054 Russia *e-mail: [email protected] Received June 7, 2020; revised June 14, 2020; accepted June 29, 2020
Abstract—N-Methyl- and N-benzyl-4H-thieno[3,2-b]pyrrole-5-carboxylic amides containing cytisine, (R)-(+)-α-methylbenzylamine, aniline, and some amino acid fragments have been synthesized. Keywords: N-methyl- and N-benzylthieno[3,2-b]pyrrole-5-carboxylic acids, aniline, L-methionine, D-alanine, (R)-(+)-α-methylbenzylamine, cytisine, amides
DOI: 10.1134/S1070428020100309 Thieno[3,2-b]pyrrolecarboxamide fragment is present in molecules of many biologically active compounds [1], including highly active inhibitors of alphaviruses. In particular, compound 1 (Fig. 1) inhibits Chikungunya viruses (CHIKV) transmitted by mosquitoes to humans [2]. Thienopyrrole 1 inhibits biosynthesis of CHIKV proteins and RNA and shows a broad spectrum of antiviral activity. Compound 2 inhibits replication of neurotropic alphaviruses such as western equine encephalitis virus [3]. Among anticancer agents, thienopyrrole 3 is a new reversible inMeO
hibitor of histone lysine demethylase KDM1A [4] which regulates balance of lysine methylation levels; search for inhibitors of that enzyme is an important line of research in cancer therapy. Thieno[3,2-b]pyrroles 4 were reported [5] as allosteric finger-loop inhibitors of the hepatitis C virus NS5B polymerase. On the whole, published data suggest prospects of search for new antiviral, anticancer, and other biologically active agents in the thienopyrrole series. In the present work we synthesized new thieno[3,2-b]pyrrole-5-carboxamides starting from N-substiF
O
O
NH
NH
O
Pr N
N
N
N
Br
Br S
S
O
O
1, EC50 = 1.96 μM
2
S
N Me
NH O
H N
O
S O
O
N
N Me
OH OMe 3, IC50 = 7.8 nM
4, IC50 = 0.019 μM
Fig. 1. Some biologically active thienopyrrolecarboxamides.
1850
Me
N
1851
NEW CARBOXAMIDES OF THE THIENO[3,2-b]PYRROLE SERIES Scheme 1. (COCl)2, DMF CH2Cl2, 0°C to r.t.
N
N R
5a, 5b
N
O
O
CH2Ph
6a
7–9
O
O 1
NR2R3
S
CH2Ph
OH
S
R2R3NH CHCl3, Δ
Cl
S
N
4'
N
N N CH2Cl2, r.t., 3–4 h
N
5'
S
6a
6
N
2
82–84% 3
3a
N R
2'
5
O 1
10a, 10b
R2R3NH CHCl3, Δ
R2 N
S N R
R3
O 1
11a, 11b
5, 10, R1 = PhCH2 (a), Me (b); 7, R2 = H, R3 = Ph; 8, R2 = H, R3 = CH(Me)Ph; 9, R2 = H, R3 = CH(CO2Me)(CH2)2SMe; O
11a, R1 = PhCH2, R2 = H, R3 = CH(CO2Me)Me; 11b, R1 = Me, R2 = H, R3= CH(CO2Me)Me; 12, R1 = Me, R2R3 =
tuted thienopyrrolecarboxylic acids 5a and 5b [6, 7] (Scheme 1). Initially, acid 5a was converted to acid chloride 6a which was treated with aniline and (R)-(+)-α-methylbenzylamine in chloroform to obtain compounds 7, 8. Amide 9 containing an L-methionine methyl ester fragment was synthesized by adding a solution of acid chloride 6a in chloroform to a mixture of L-methionine methyl ester hydrochloride and pyridine, co
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