- Design, Synthesis, and Docking Studies of Thioimidazolyl Diketoacid Derivatives Targeting HIV-1 Integrase
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Background: Integrase enzyme is a validated drug target to discover novel structures as anti-HIV-1 agents. Objective: This study aimed at developing a novel series of thioimidazolyl diketoacid derivatives characterizing various substituents at N-1 and 2-thio positions of the central ring as HIV-1integrase inhibitors. Methods: In this study, eighteen novel thioimidazolyl DKA derivatives were synthesized in a five-step parallel procedure and tested in vitro for the inhibition of both IN ST reaction and the single-cycle HIV-1 replication in HeLa cell culture. Results: The obtained molecules were evaluated using the enzyme assay, displaying promising integrase inhibitory activity with IC50 values ranging from 0.9 to 7.7 mM. The synthesized compounds were also tested for antiviral activity and cytotoxicity using HeLa cells infected by the single-cycle replicable HIV-1 NL4-3. Conclusion: The most potent compound was found to be 18i with EC50 = 19 μM, IC50 = 0.9 μM, and SI = 10.5. Docking studies indicated that the binding mode of the active molecule is well aligned with the known HIV-1integrase inhibitor.
- Hajimahdi, Zahra,Karimi, Nafiseh,Roudsari, Rouhollah Vahabpour,Zarghi, Afshin
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p. 616 - 628
(2022/03/09)
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- 4,5-Disubstituted N-Methylimidazoles as Versatile Building Blocks for Defined Side-Chain Introduction
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Fungerin is a 1,4,5-trisubstituted imidazole natural product characterised by a broad spectrum of antifungal activities. We planned to develop flexible strategies to access to such compounds. Imidazoles bearing suitable anchor groups at C-4 and C-5 allow the introduction of various substituted side-chains, generating libraries of fungerin derivatives for biological tests. Starting from commercially available reactants, two N-methyl 4,5-substituted imidazole core units were synthesised. Derivatives of type 1 contained two orthogonally protected C-1 anchors. Selective side-chain introduction was achieved through a sequence of Grignard coupling at C-5 to replace a tosylate and a Horner olefination through an aldehyde attached to C-4. Two target fungerin derivatives were synthesised. Since the organometallic substitution of the C-5-CH2-positioned leaving group proved to suffer from limitations concerning potential competing side-reactions, a type 2 imidazole core was built up. These structures had a halogen centre at C-4 and a hydroxyethyl anchor at C-5. Now, selective side-chain introduction allowed us to use Julia olefination to form the allyl side-chain at C-5 and Heck reactions to introduce the C-4 acryl substituents. Eight derivatives, including fungerin, were synthesised by this latter strategy, without producing any regioisomers. The second approach had the advantage that various side-chains could be coupled at C-4 and C-5 in two final steps. Thus, this strategy represents a versatile way to build up libraries of fungerin derivatives for biological testing.
- Przybyla, Daniel,Nubbemeyer, Udo
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supporting information
p. 695 - 703
(2017/02/05)
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- Synthesis and antiproliferative activity evaluation of imidazole-based indeno[1,2-b]quinoline-9,11-dione derivatives
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A series of new imidazole substituted indeno[1,2-b]quinoline-9,11-dione derivatives were synthesized and evaluated for their antiproliferative effects on HeLa, LS180, MCF-7 and Jurkat human cancer cell lines. Antiproliferative effects were evaluated using MTT assay. Prepared compounds exhibited weak to good antiproliferative activity in evaluated cell lines. Prepared compounds were more potent in Jurkat cell line when compared to LS180, HeLa and MCF-7 cell lines. Compounds 29 (IC16 = 0.7 μM) and 31 (IC16 = 1.7 μM) and 33 (IC16 = 1.7 μM) were found to be the most potent molecules on Jurkat cell lines. Moreover; it was found that some of the tested compounds bearing imidazole-2-yl moiety on the C11-position of dihydropyridine ring exhibited superior antiproliferative activity in comparison to cis-platin especially in Jurkat cell line (compounds 29, 31, and 33). It seemed that the introduction of electron-withdrawing groups on the imidazole ring enhanced the antiproliferative potential of these compounds (compounds 27, 29 and 31). The results of this study proposed that some of the imidazole substituted indeno[1,2-b]quinoline-9,11-dione compounds may act as efficient anticancer agents in vitro, emphasizing their potential role as a source for rational design of potent antiproliferative agents.
- Sarkarzadeh, Hasti,Miri, Ramin,Firuzi, Omidreza,Amini, Mohsen,Razzaghi-Asl, Nima,Edraki, Najmeh,Shafiee, Abbas
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p. 436 - 447
(2013/07/28)
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- Azaindoles
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The invention is directed to compositions containing physiologically active compounds of general formula (I): wherein R1 is aryl or heteroaryl; R2 represents hydrogen, acyl, cyano, halo, lower alkenyl or lower alkyl optionally substituted by a substituent selected from cyano, heteroaryl, heterocycloalkyl, —Z1R8, —C(═O)—NY3Y4, —CO2R8, —NY3Y4, —N(R6)—C(═O)—R7, —N(R6)—C(═O)—NY3Y4, —N(R6)—C(═O)—OR7, —N(R6)—SO2—R7, —N(R6)—SO2—NY3Y4 and one or more halogen a toms ; R3 represents hydrogen, aryl, cyano, halo, heteroaryl, lower alkyl, —C(═O)—OR5 or —C(═O)—NY3Y; and X1 represents N, CH, C-halo, C—CN, C—R7, C—NY3Y4, C—OH, C—Z2R7, C—C(═O)—OR5, C—C(═O)—NY3Y4, C—N(R8)—C(═O)—R7, C—SO2—NY3Y4, C—N(R8)—SO2—R7, C-alkenyl, C-alkynyl or C—NO2; and their prodrugs, and pharmaceutically acceptable salts and solvates of such compounds and their prodrugs, as well as to novel compounds within the scope of formula (I). Such compounds and compositions have valuable pharmaceutical properties, in particular the ability to inhibit protein kinases.
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Page/Page column 117
(2008/06/13)
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- Synthesis and anti-inflammatory activity of new 1-methyl-4-(4-X-benzenesulfonyl)pyrrolo[2,3-d] imidazole-5-carboxylates
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A series of 1-methyl-4-(4-X-arylsulfonyl)pyrrolo[2,3-d]imidazole-5-carboxylates were synthesized and tested as anti-inflammatory agents. Indomethacin was used as reference drug. Two of the synthesized compounds 7a and 7b had an effect equal to 0.1 of indomethacin. Our result showed that the electron-withdrawing substituents in the para position of the benzensulfonyl moiety increase activity.
- Zarghi,Ebrahimabadi,Hassanzadeh,Heydari,Shafiee
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p. 251 - 254
(2007/10/03)
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- Preparation and structure determination of 1-benzyl-, 1-methyl- and 1H-5-[(2-nitro-2-phenyl)ethenyl]imidazoles
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1-R-5-[(2-Nitro-2-phenyl)ethenyl]imidazoles (R = Bn, Me, H) 6a,b,c were synthesized by the Knoevenagel reaction of the corresponding aldehydes 4a,b,c with phenylnitromethane 5. The E-isomers 6a,b,c were precipitated from the reaction mixture as crystalline compounds in 89, 81 and 60% yields, respectively. Traces of the Z-isomers 6a'b',c' were found in the reaction mixtures but could be obtained in a ratio of 4:3 from the E-form with UV irradiation. The E-forms were more stable and the Z-isomers changed again to the E-isomers in several weeks.
- Aulaskari, Paula,Ahlgren, Markku,Rouvinen, Juha,Vainiotalo, Pirjo,Pohjala, Esko,Vepsaelaeinen, Jouko
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p. 1345 - 1354
(2007/10/03)
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- An Effective Chirospecific Synthesis of (+)-Pilocarpine from L-Aspartic Acid
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A short and efficient synthesis of (+)-pilocarpine (1) has been accomplished in 10 steps and 51percent overall yield from L-aspartic acid.The synthesis features a diastereoselective alkylation of a protected aspartic acid diester derivative and a selective hydrolysis of the α-methyl ester to give the corresponding amino acid.Subsequent replacement of the amino group with bromo, esterification, and a modified Reformatsky reaction with 1-methylimidazole-5-carboxaldehyde (8) afforded imidazole-substituted lactone 28.Details concerning this novel lactone synthesis are also described.Finally, hydrogenolysis of the lactone carbon-oxygen bond and selective reduction of the resulting monoester afforded pure (+)-pilocarpine (1).
- Dener, Jeffrey M.,Zhang, Lin-Hua,Rapoport, Henry
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p. 1159 - 1166
(2007/10/02)
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