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How to cite this paper
APA: Nechesnyi, Y., Kemskyi, S., Grozav, A., Yakovychuk, N., Yutilova, K., Melnyk, D & Vovk, M. (2026). Pyrrolo[1,2-a]pyrazine-4,7-dicarboxylates: Synthesis, structural modification, bioactivity prediction, antimicrobial properties, and docking studies. Current Chemistry Letters, 15(1), 1-16.
Chicago/Turabian: Nechesnyi, Y., Kemskyi, S., Grozav, A., Yakovychuk, N., Yutilova, K., Melnyk, D & Vovk, M. 2026. "Pyrrolo[1,2-a]pyrazine-4,7-dicarboxylates: Synthesis, structural modification, bioactivity prediction, antimicrobial properties, and docking studies." Current Chemistry Letters 15, no. 1 (2026): 1-16.
AMA: Nechesnyi, Y., Kemskyi, S., Grozav, A., Yakovychuk, N., Yutilova, K., Melnyk, D & Vovk, M. Pyrrolo[1,2-a]pyrazine-4,7-dicarboxylates: Synthesis, structural modification, bioactivity prediction, antimicrobial properties, and docking studies. Current Chemistry Letters. 2026;15(1):1-16.
References
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2 De la Torre B. G., and Albericio F. (2025) The Pharmaceutical Industry in 2024: An Analysis of the FDA Drug Approvals from the Perspective of Molecules. Molecules, 30 (3) 482. DOI: 10.3390/molecules30030482
3 Mitra A. K., and Ghosh A. (2025). Perspective of Biginelli Reaction: EN Route toward the Development of Biologically and Industrially Relevant Dyhidropyrimidone-Based Frameworks. Chem. Heterocycl. Comp., 61 (5-6) 155-187.
4 Levchenko, K., and Pokhodylo, N. (2025). Bicyclic pyrrolidines: recent advances and emerging trends (microreview). Chem. Heterocycl. Comp. 61 (3-4) 133–135. DOI: 10.1007/s10593-025-03404-9
5 Klenina, O. V., Chaban, T. I., Chaban, I. H., and Lelyukh, M. I. (2025). Recent advances in the synthesis of thiazolo[4,5-b]pyridines. Part 3. Focus on biological activity (microreview). Chem. Heterocycl. Comp., 61 (1-2) 57–60. DOI: 10.1007/s10593-025-03398-4
6 Ritchie T. J., Macdonald S. J. F., Young R. J., and Pickett S. D. (2011) The Impact of Aromatic Ring Count on Compound Developability: Further Insights by Examining Carbo- and Hetero-Aromatic and -Aliphatic Ring Types. Drug Discov. Today, 16 (3–4) 164–171. DOI: 10.1016/j.drudis.2010.11.014
7 Winant P., Horsten T., Gil de Melo S., Emery F., and Dehaen, W. (2021) A Review of the Synthetic Strategies toward Dihydropyrrolo[1,2-a]Pyrazinones. Organics, 2 (2) 118–141. DOI: 10.3390/org2020011
8 Arban R., Bianchi F., Buson A., Cremonesi S., Fabio R. Di, Gentile G., Micheli F., Pasquarello A., Pozzan, A., Tarsi L., Terreni S., and Tonelli F. (2010) Pyrrolo[1,2-a]Pyrazine and Pyrazolo[1,5-a]Pyrazine: Novel, Potent, and Selective Series of Vasopressin 1b Receptor Antagonists. Bioorg. Med. Chem. Lett., 20 (17) 5044–5049. DOI: 10.1016/j.bmcl.2010.07.037
9 Micheli F., Bertani B., Bozzoli A., Crippa L., Cavanni P., Di Fabio R., Donati D., Marzorati P., Merlo G., Paio A., Perugini L., and Zarantonello P. (2008) Phenylethynyl-Pyrrolo[1,2-a]Pyrazine: A New Potent and Selective Tool in the MGluR5 Antagonists Arena. Bioorg. Med. Chem. Lett., 18 (6) 1804–1809. DOI: 10.1016/j.bmcl.2008.02.024
10 Bernat V. J., Alonso Diez J. A., Buil Albero M. A., Eastwood P. R., Esteve Trias C., Lozoya Toribio M. E., Roberts R. S., Vidal Gisbert L., Gonzalez Rodriguez J., and Mir Cepeda M. (2013) New CRTh2 Antagonists. WO Patent 2013/010880.
11 Ohtani M., Fuji M., and Okada T. (2002) Pyrrolo[1,2-a]pyrazine sPLA2 inhibitor. US Patent 6,407,104.
12 Zhang M., Jang H., and Nussinov R. (2020) PI3K Inhibitors: Review and New Strategies. Chem. Sci., 11 (23) 5855–5865. DOI: 10.1039/D0SC01676D
13 Kim J., Park M., Choi J., Singh D. K., Kwon H. J., Kim S. H., and Kim, I. (2019) Design, Synthesis, and Biological Evaluation of Novel Pyrrolo[1,2-a]Pyrazine Derivatives. Bioorg. Med. Chem. Lett., 29 (11) 1350–1356. DOI: 10.1016/j.bmcl.2019.03.044
14 Sasaki T., Kanematsu K., Yukimoto Y., and Ochiai, S. (1971) Heteroaromaticity. XLIII. Orientation in the 1,3-Dipolar Cycloaddition Reactions of Heteroaromatic Nitrogen Methylides with Dipolarophiles. J. Org. Chem., 36 (6) 813–818. DOI: 10.1021/jo00805a018
15 Howell A. R., Martin W. R., Sloan J. W., and Smith, W. T. (1991) Synthesis and Binding Activity of 4-azanicotine. J. Heterocycl. Chem., 28 (4) 1147–1151. DOI: 10.1002/jhet.5570280453
16 He C., Wang Z., Chen Y., Zhang G. and Yu Y. (2021) Palladium(II)-Catalyzed C(sp)–C(sp2) Coupling: A Direct Approach to Multi-Substituted Pyrrolo[1,2-a]Pyrazines. Synthesis, 53 (12) 2051–2056. DOI: 10.1055/s-0040-1706644
17 Anderson C. E., Bos H. I., Dreher D. M., Hartgerink C. T., Scholtens, C. J., and Staples, R. J. (2022) Synthesis of Ester-Substituted Indolizines from 2-Propargyloxypyridines and 1,3-Dicarbonyls. J. Org. Chem., 87 (15) 10241–10249. DOI: 10.1021/acs.joc.2c01219
18 Amărandi R.-M., Al-Matarneh M.-C., Popovici L., Ciobanu C. I., Neamțu A., Mangalagiu I. I., and Danac, R. (2023) Exploring Pyrrolo-Fused Heterocycles as Promising Anticancer Agents: An Integrated Synthetic, Biological, and Computational Approach. Pharmaceuticals, 16 (6) 865. DOI: 10.3390/ph16060865
19 Chen W., Hu M., Wu J., Zou H., and Yu, Y. (2010) Domino Approach for the Synthesis of Pyrrolo[1,2-α]Pyrazine from Vinyl Azides. Org. Lett., 12 (17) 3863–3865. DOI: 10.1021/ol101538x
20 Mokrov G. V., Deeva O. A., Gudasheva T. A., Yarkov S. A., Yarkova M. A., and Seredenin S. B. (2015) Design, Synthesis and Anxiolytic-like Activity of 1-Arylpyrrolo[1,2-a]Pyrazine-3-Carboxamides. Bioorg. Med. Chem., 23 (13) 3368–3378. DOI: 10.1016/j.bmc.2015.04.049
21 Charvin D., Pomel V., Ortiz M., Frauli M., Scheffler S., Steinberg E., Baron L., Deshons L., Rudigier R., Thiarc D., Morice C., Manteau B., Mayer S., Graham D., Giethlen B., Brugger N., Hédou G., Conquet F., and Schann S. (2017) Discovery, Structure–Activity Relationship, and Antiparkinsonian Effect of a Potent and Brain-Penetrant Chemical Series of Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4. J. Med. Chem., 60 (20) 8515–8537. DOI: 10.1021/acs.jmedchem.7b00991
22 Karmakar A., Ramalingam S., Basha M., Indasi G. K., Belema M., Meanwell N. A., Dhar T. G. M., Rampulla R., Mathur A., Gupta A., and Gupta A. K. (2020) Facile Access to 1,4-Disubstituted Pyrrolo[1,2-a]pyrazines from α-Aminoacetonitriles. Synthesis, 52 (03) 441–449. DOI: 10.1055/s-0039-1690699
23 Miranda-Sánchez D., Escalante C. H., Andrade-Pavón D., Gómez-García O., Barrera E., Villa-Tanaca L., Delgado F., and Tamariz J. (2023) Pyrrole-Based Enaminones as Building Blocks for the Synthesis of Indolizines and Pyrrolo[1,2-a]pyrazines Showing Potent Antifungal Activity. Molecules, 28 (20) 7223. DOI: 10.3390/molecules28207223
24 Berner H., Schulz G., and Reinshagen H. (1977) Synthese Der 5-Arylpyrromethene. Monatshefte für Chemie, 108 (2) 285–297. DOI: 10.1007/BF00901980
25 Jin Y.-Z., Fu D.-X., Ma N., Li Z.-C., Liu Q.-H., Xiao L., and Zhang R.-H. (2011) Synthesis and Biological Evaluation of 3-Substituted-indolin-2-one Derivatives Containing Chloropyrrole Moieties. Molecules, 16 (11) 9368–9385. DOI: 10.3390/molecules16119368
26 Reinus B., and Kerwin S. A. (2017) Copper-Catalyzed N-Alkynylation Route to 2-Substituted N-Alkynyl Pyrroles and Their Cyclization into Pyrrolo[2,1-c]oxazin-1-ones: A Formal Total Synthesis of Peramine. Synthesis, 49 (11), 2544–2554. DOI: 10.1055/s-0036-1588736
27 Miyaura N., and Suzuki A. (1995). Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chem. Rev., 95 (7), 2457–2483. DOI: 10.1021/cr00039a007
28 Demchuk, O. M., Kapłon, K., Kącka, A., and Pietrusiewicz, K. M. (2016). The utilization of chiral phosphorus ligands in atroposelective cross-coupling reactions. Phosphorus, Sulfur, and Silicon and the Related Elements, 191 (2) 180–200. DOI: 10.1080/10426507.2015.1079197
29 Sonogashira K. (2002) Development of Pd–Cu Catalyzed Cross-Coupling of Terminal Acetylenes with sp2-Carbon Halides. J. Organomet. Chem., 653 (1–2) 46–49. DOI: 10.1016/S0022-328X(02)01158-0
30 Sayiner H.S., Yilmazer M.I, Abdelsalam A.T., Ganim M.A., Baloglu C., Altunoglu Y.C., Gür M., Saracoglu M., Attia M.S., Mahmoud S.A., Mohamed E.H., Boukherroub R., Al-Shaalan N.H., Alharthi S., Kandemirli F., Amin M.A. (2022). Synthesis and characterization of new 1,3,4-thiadiazole derivatives: study of their antibacterial activity and CT-DNA binding. RSC Adv., 12, 29627-29639. DOI: 10.1039/D2RA02435G
31 Cotman A.E., Fulgheri F., Piga M., Persolia P., Tiz D.B., Skok Z., Dursik M., Sterle M., Dernovsek J., Cruz D., Mammela P., Szill P.E., Daruka L., Pal C., Zega A., Mosic L.P., Ilas J., Tomasic T., Kikelj D., Zidar N (2024). New N-phenylpyrrolamide inhibitors of DNA gyrase with improved antibacterial activity. RSC Adv. 14, 28423-28454. DOI: 10.1039/D4RA04802D
32 Kowalska-Krochmal B., and Dudek-Wicher R. (2021). The minimum inhibitory concentration of antibiotics: methods, interpretation, clinical relevance. Pathogens, 10 (2), 165. DOI: 10.3390/pathogens10020165
33 Nazarchuk O. A. (2016). Antiseptics: modern strategy of struggle with causing agents of the іnfection complications. Klin Khir., 9, 59-61.
34 Crowley P.D., and Gallagher H.C. (2014). Clotrimazole as a pharmaceutical: past, present and future. J. Appl. Microbiol., 117 (3) 611-617. DOI: 10/1111/jam.12554
35 Eberhardt J., Santos-Martins D., Tillack A.F., Forli S. (2021). AutoDock 1.2.0: New Docking Methods, Expanded Force Field, and Python Binding. J. Chem. Inform. Model., 61 (8), 3891-3898. DOI: 10.1021/acs.jcim.1c00203
36 Marris G.M., Huey R., Lindstrom W., Sanner M.F., Belew R.K., Goodsell D.S., Olson A.J. (2009). AutoDock 4 and AutoDocd Tools 4: Automated docking with selective receptor flexibility. Comput. Chem., 30 (16), 2785-2791. DOI: 10.1002/jcc.21256
2 De la Torre B. G., and Albericio F. (2025) The Pharmaceutical Industry in 2024: An Analysis of the FDA Drug Approvals from the Perspective of Molecules. Molecules, 30 (3) 482. DOI: 10.3390/molecules30030482
3 Mitra A. K., and Ghosh A. (2025). Perspective of Biginelli Reaction: EN Route toward the Development of Biologically and Industrially Relevant Dyhidropyrimidone-Based Frameworks. Chem. Heterocycl. Comp., 61 (5-6) 155-187.
4 Levchenko, K., and Pokhodylo, N. (2025). Bicyclic pyrrolidines: recent advances and emerging trends (microreview). Chem. Heterocycl. Comp. 61 (3-4) 133–135. DOI: 10.1007/s10593-025-03404-9
5 Klenina, O. V., Chaban, T. I., Chaban, I. H., and Lelyukh, M. I. (2025). Recent advances in the synthesis of thiazolo[4,5-b]pyridines. Part 3. Focus on biological activity (microreview). Chem. Heterocycl. Comp., 61 (1-2) 57–60. DOI: 10.1007/s10593-025-03398-4
6 Ritchie T. J., Macdonald S. J. F., Young R. J., and Pickett S. D. (2011) The Impact of Aromatic Ring Count on Compound Developability: Further Insights by Examining Carbo- and Hetero-Aromatic and -Aliphatic Ring Types. Drug Discov. Today, 16 (3–4) 164–171. DOI: 10.1016/j.drudis.2010.11.014
7 Winant P., Horsten T., Gil de Melo S., Emery F., and Dehaen, W. (2021) A Review of the Synthetic Strategies toward Dihydropyrrolo[1,2-a]Pyrazinones. Organics, 2 (2) 118–141. DOI: 10.3390/org2020011
8 Arban R., Bianchi F., Buson A., Cremonesi S., Fabio R. Di, Gentile G., Micheli F., Pasquarello A., Pozzan, A., Tarsi L., Terreni S., and Tonelli F. (2010) Pyrrolo[1,2-a]Pyrazine and Pyrazolo[1,5-a]Pyrazine: Novel, Potent, and Selective Series of Vasopressin 1b Receptor Antagonists. Bioorg. Med. Chem. Lett., 20 (17) 5044–5049. DOI: 10.1016/j.bmcl.2010.07.037
9 Micheli F., Bertani B., Bozzoli A., Crippa L., Cavanni P., Di Fabio R., Donati D., Marzorati P., Merlo G., Paio A., Perugini L., and Zarantonello P. (2008) Phenylethynyl-Pyrrolo[1,2-a]Pyrazine: A New Potent and Selective Tool in the MGluR5 Antagonists Arena. Bioorg. Med. Chem. Lett., 18 (6) 1804–1809. DOI: 10.1016/j.bmcl.2008.02.024
10 Bernat V. J., Alonso Diez J. A., Buil Albero M. A., Eastwood P. R., Esteve Trias C., Lozoya Toribio M. E., Roberts R. S., Vidal Gisbert L., Gonzalez Rodriguez J., and Mir Cepeda M. (2013) New CRTh2 Antagonists. WO Patent 2013/010880.
11 Ohtani M., Fuji M., and Okada T. (2002) Pyrrolo[1,2-a]pyrazine sPLA2 inhibitor. US Patent 6,407,104.
12 Zhang M., Jang H., and Nussinov R. (2020) PI3K Inhibitors: Review and New Strategies. Chem. Sci., 11 (23) 5855–5865. DOI: 10.1039/D0SC01676D
13 Kim J., Park M., Choi J., Singh D. K., Kwon H. J., Kim S. H., and Kim, I. (2019) Design, Synthesis, and Biological Evaluation of Novel Pyrrolo[1,2-a]Pyrazine Derivatives. Bioorg. Med. Chem. Lett., 29 (11) 1350–1356. DOI: 10.1016/j.bmcl.2019.03.044
14 Sasaki T., Kanematsu K., Yukimoto Y., and Ochiai, S. (1971) Heteroaromaticity. XLIII. Orientation in the 1,3-Dipolar Cycloaddition Reactions of Heteroaromatic Nitrogen Methylides with Dipolarophiles. J. Org. Chem., 36 (6) 813–818. DOI: 10.1021/jo00805a018
15 Howell A. R., Martin W. R., Sloan J. W., and Smith, W. T. (1991) Synthesis and Binding Activity of 4-azanicotine. J. Heterocycl. Chem., 28 (4) 1147–1151. DOI: 10.1002/jhet.5570280453
16 He C., Wang Z., Chen Y., Zhang G. and Yu Y. (2021) Palladium(II)-Catalyzed C(sp)–C(sp2) Coupling: A Direct Approach to Multi-Substituted Pyrrolo[1,2-a]Pyrazines. Synthesis, 53 (12) 2051–2056. DOI: 10.1055/s-0040-1706644
17 Anderson C. E., Bos H. I., Dreher D. M., Hartgerink C. T., Scholtens, C. J., and Staples, R. J. (2022) Synthesis of Ester-Substituted Indolizines from 2-Propargyloxypyridines and 1,3-Dicarbonyls. J. Org. Chem., 87 (15) 10241–10249. DOI: 10.1021/acs.joc.2c01219
18 Amărandi R.-M., Al-Matarneh M.-C., Popovici L., Ciobanu C. I., Neamțu A., Mangalagiu I. I., and Danac, R. (2023) Exploring Pyrrolo-Fused Heterocycles as Promising Anticancer Agents: An Integrated Synthetic, Biological, and Computational Approach. Pharmaceuticals, 16 (6) 865. DOI: 10.3390/ph16060865
19 Chen W., Hu M., Wu J., Zou H., and Yu, Y. (2010) Domino Approach for the Synthesis of Pyrrolo[1,2-α]Pyrazine from Vinyl Azides. Org. Lett., 12 (17) 3863–3865. DOI: 10.1021/ol101538x
20 Mokrov G. V., Deeva O. A., Gudasheva T. A., Yarkov S. A., Yarkova M. A., and Seredenin S. B. (2015) Design, Synthesis and Anxiolytic-like Activity of 1-Arylpyrrolo[1,2-a]Pyrazine-3-Carboxamides. Bioorg. Med. Chem., 23 (13) 3368–3378. DOI: 10.1016/j.bmc.2015.04.049
21 Charvin D., Pomel V., Ortiz M., Frauli M., Scheffler S., Steinberg E., Baron L., Deshons L., Rudigier R., Thiarc D., Morice C., Manteau B., Mayer S., Graham D., Giethlen B., Brugger N., Hédou G., Conquet F., and Schann S. (2017) Discovery, Structure–Activity Relationship, and Antiparkinsonian Effect of a Potent and Brain-Penetrant Chemical Series of Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4. J. Med. Chem., 60 (20) 8515–8537. DOI: 10.1021/acs.jmedchem.7b00991
22 Karmakar A., Ramalingam S., Basha M., Indasi G. K., Belema M., Meanwell N. A., Dhar T. G. M., Rampulla R., Mathur A., Gupta A., and Gupta A. K. (2020) Facile Access to 1,4-Disubstituted Pyrrolo[1,2-a]pyrazines from α-Aminoacetonitriles. Synthesis, 52 (03) 441–449. DOI: 10.1055/s-0039-1690699
23 Miranda-Sánchez D., Escalante C. H., Andrade-Pavón D., Gómez-García O., Barrera E., Villa-Tanaca L., Delgado F., and Tamariz J. (2023) Pyrrole-Based Enaminones as Building Blocks for the Synthesis of Indolizines and Pyrrolo[1,2-a]pyrazines Showing Potent Antifungal Activity. Molecules, 28 (20) 7223. DOI: 10.3390/molecules28207223
24 Berner H., Schulz G., and Reinshagen H. (1977) Synthese Der 5-Arylpyrromethene. Monatshefte für Chemie, 108 (2) 285–297. DOI: 10.1007/BF00901980
25 Jin Y.-Z., Fu D.-X., Ma N., Li Z.-C., Liu Q.-H., Xiao L., and Zhang R.-H. (2011) Synthesis and Biological Evaluation of 3-Substituted-indolin-2-one Derivatives Containing Chloropyrrole Moieties. Molecules, 16 (11) 9368–9385. DOI: 10.3390/molecules16119368
26 Reinus B., and Kerwin S. A. (2017) Copper-Catalyzed N-Alkynylation Route to 2-Substituted N-Alkynyl Pyrroles and Their Cyclization into Pyrrolo[2,1-c]oxazin-1-ones: A Formal Total Synthesis of Peramine. Synthesis, 49 (11), 2544–2554. DOI: 10.1055/s-0036-1588736
27 Miyaura N., and Suzuki A. (1995). Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chem. Rev., 95 (7), 2457–2483. DOI: 10.1021/cr00039a007
28 Demchuk, O. M., Kapłon, K., Kącka, A., and Pietrusiewicz, K. M. (2016). The utilization of chiral phosphorus ligands in atroposelective cross-coupling reactions. Phosphorus, Sulfur, and Silicon and the Related Elements, 191 (2) 180–200. DOI: 10.1080/10426507.2015.1079197
29 Sonogashira K. (2002) Development of Pd–Cu Catalyzed Cross-Coupling of Terminal Acetylenes with sp2-Carbon Halides. J. Organomet. Chem., 653 (1–2) 46–49. DOI: 10.1016/S0022-328X(02)01158-0
30 Sayiner H.S., Yilmazer M.I, Abdelsalam A.T., Ganim M.A., Baloglu C., Altunoglu Y.C., Gür M., Saracoglu M., Attia M.S., Mahmoud S.A., Mohamed E.H., Boukherroub R., Al-Shaalan N.H., Alharthi S., Kandemirli F., Amin M.A. (2022). Synthesis and characterization of new 1,3,4-thiadiazole derivatives: study of their antibacterial activity and CT-DNA binding. RSC Adv., 12, 29627-29639. DOI: 10.1039/D2RA02435G
31 Cotman A.E., Fulgheri F., Piga M., Persolia P., Tiz D.B., Skok Z., Dursik M., Sterle M., Dernovsek J., Cruz D., Mammela P., Szill P.E., Daruka L., Pal C., Zega A., Mosic L.P., Ilas J., Tomasic T., Kikelj D., Zidar N (2024). New N-phenylpyrrolamide inhibitors of DNA gyrase with improved antibacterial activity. RSC Adv. 14, 28423-28454. DOI: 10.1039/D4RA04802D
32 Kowalska-Krochmal B., and Dudek-Wicher R. (2021). The minimum inhibitory concentration of antibiotics: methods, interpretation, clinical relevance. Pathogens, 10 (2), 165. DOI: 10.3390/pathogens10020165
33 Nazarchuk O. A. (2016). Antiseptics: modern strategy of struggle with causing agents of the іnfection complications. Klin Khir., 9, 59-61.
34 Crowley P.D., and Gallagher H.C. (2014). Clotrimazole as a pharmaceutical: past, present and future. J. Appl. Microbiol., 117 (3) 611-617. DOI: 10/1111/jam.12554
35 Eberhardt J., Santos-Martins D., Tillack A.F., Forli S. (2021). AutoDock 1.2.0: New Docking Methods, Expanded Force Field, and Python Binding. J. Chem. Inform. Model., 61 (8), 3891-3898. DOI: 10.1021/acs.jcim.1c00203
36 Marris G.M., Huey R., Lindstrom W., Sanner M.F., Belew R.K., Goodsell D.S., Olson A.J. (2009). AutoDock 4 and AutoDocd Tools 4: Automated docking with selective receptor flexibility. Comput. Chem., 30 (16), 2785-2791. DOI: 10.1002/jcc.21256