Síntese e avaliação de licochalcona H (LCH) e seus análogos como potenciais agentes antibacterianos e antimicobacterianos
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2022-04-03
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Universidade Estadual Paulista (Unesp)
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Com o crescente desenvolvimento de resistência aos fármacos antibacterianos, as infecções microbianas mais comuns vêm se tornando um grande risco e desafio para saúde pública. A licochalcona H (LCH) foi selecionada como protótipo para o planejamento de três séries de análogos a serem sintetizados e avaliados contra bactérias e micobactérias patogênicas humanas. A LCH é uma retrochalcona C-isoprenilada, sendo um isômero constitucional da licochalcona A (LCA) e da licochalcona C (LCC), isoladas das raízes de Glycyrrhiza glabra (regaliz ou alcaçuz). A série I visa a avaliação de análogos modificados no anel A, permitindo avaliar a relevância da presença e posição da hidroxila e de substituintes eletrodoadores e eletroatratores. As modificações com relação ao substituinte isoprenila do anel B compõem a série II de análogos. A série III é composta pelas reduções parcial e total da cetona α, β-insaturada de LCH. Até o momento foram sintetizadas 35 substâncias, sendo 24 intermediários e 11 produtos finais, sendo eles a LCH, dois produtos naturais (equinatina e loureirina C) e os demais são inéditos na literatura. Para obtenção dos produtos finais desenvolveu-se uma rota sintética inédita que inclui reações de proteção com grupo metoximetila, O-metilação, iodação regiosseletiva, condensação aldólica de Claisen-Schmidt, acoplamento de Suzuki-Miyaura, desproteção e redução de carbonila α, β-insaturada. LCH, equinatina (ECH) e 7 se mostraram ativos contra bactérias Gram-positivas, micobactérias e inativas contra Gram-negativas, exceto contra Helicobacter pylori, com valores de Concentração Inibitória Mínima capaz de inibir pelo menos 90% dos micro-organismos (CIM90) variando de 9,2 – 1480 μM. 7, um regioisômero de LCH, apresentou uma potência aumentada, em comparação com o protótipo, em até 8 vezes contra bactérias Gram-positivas e em até 2 vezes contra micobactérias. Por outro lado 7, foi 3 vezes menos ativa que LCH contra H. pylori. Dos análogos avaliados biologicamente da série I, 7 foi o único que apresentou atividade significante comparado aos controles positivos (tetraciclina e clorexidina), o que indica que a hidroxila no anel A possui contribuição farmacofórica. Contra as micobactérias a ECH foi destaque, considerando sua simplicidade sintética, demonstrando valores de CIM90 variando de 115,6 – 231,2 μM.
With the increasing development of resistance to antibacterial drugs, the most common microbial infections have become a major risk and challenge for public health. Licochalcone H (LCH) was selected as a prototype for the design of three series of analogues to be synthesized and evaluated against human pathogenic bacteria and mycobacteria. LCH is a C-isoprenylated retrochalcone, a constitutional isomer of licochalcone A (LCA) and licochalcone C (LCC), isolated from the roots of Glycyrrhiza gabra (regalis or licorice). The series I aims at the evaluation of modified analogues in the A ring, allowing to evaluate the relevance of the presence and position of the hydroxyl and electron donor-acceptor substituents. Modifications with respect to the isoprenyl substituent of B ring compose the series II of analogues. Series III is composed of partial and total reductions of the α, β unsaturated ketone of LCH. So far, 35 substances have been synthesized, 24 of which are intermediates and 11 are final products, being LCH, two natural products (echinatin and loureirin C) and the others are unpublished in the literature. To obtain the final products, an unprecedented synthetic route was developed that includes protection reactions with methoxymethyl group, O-methylation, regioselective iodination, Claisen-Schmidt aldol condensation, Suzuki-Miyaura coupling, deprotection and reduction of α, β unsaturated carbonyl. LCH, echinatin (ECH) and 7 were active against Gram-positive bacteria, mycobacteria and inactive against Gram-negative bacteria, except against Helicobacter pylori, with minimum inhibitory concentration values capable of inhibiting at least 90% of microorganisms (MIC90) ranging from 9,2 – 1480 μM. 7, a regioisomer of LCH, showed an increased potency compared to the prototype, up to 8 times against Gram-positive bacteria and up to 2 times against mycobacteria. On the other hand, 7 was 3 times less active than LCH against H. pylori. Of the biologically evaluated analogues of series I, 7 was the only one that showed significant activity compared to positive controls (tetracycline and chlorhexidine), which indicates that hydroxyl group in the A ring has a pharmacophoric contribution. Against mycobacteria, ECH was the highlight, considering its synthetic simplicity, showing MIC90 values ranging from 115,6 – 231,2 μM.
With the increasing development of resistance to antibacterial drugs, the most common microbial infections have become a major risk and challenge for public health. Licochalcone H (LCH) was selected as a prototype for the design of three series of analogues to be synthesized and evaluated against human pathogenic bacteria and mycobacteria. LCH is a C-isoprenylated retrochalcone, a constitutional isomer of licochalcone A (LCA) and licochalcone C (LCC), isolated from the roots of Glycyrrhiza gabra (regalis or licorice). The series I aims at the evaluation of modified analogues in the A ring, allowing to evaluate the relevance of the presence and position of the hydroxyl and electron donor-acceptor substituents. Modifications with respect to the isoprenyl substituent of B ring compose the series II of analogues. Series III is composed of partial and total reductions of the α, β unsaturated ketone of LCH. So far, 35 substances have been synthesized, 24 of which are intermediates and 11 are final products, being LCH, two natural products (echinatin and loureirin C) and the others are unpublished in the literature. To obtain the final products, an unprecedented synthetic route was developed that includes protection reactions with methoxymethyl group, O-methylation, regioselective iodination, Claisen-Schmidt aldol condensation, Suzuki-Miyaura coupling, deprotection and reduction of α, β unsaturated carbonyl. LCH, echinatin (ECH) and 7 were active against Gram-positive bacteria, mycobacteria and inactive against Gram-negative bacteria, except against Helicobacter pylori, with minimum inhibitory concentration values capable of inhibiting at least 90% of microorganisms (MIC90) ranging from 9,2 – 1480 μM. 7, a regioisomer of LCH, showed an increased potency compared to the prototype, up to 8 times against Gram-positive bacteria and up to 2 times against mycobacteria. On the other hand, 7 was 3 times less active than LCH against H. pylori. Of the biologically evaluated analogues of series I, 7 was the only one that showed significant activity compared to positive controls (tetracycline and chlorhexidine), which indicates that hydroxyl group in the A ring has a pharmacophoric contribution. Against mycobacteria, ECH was the highlight, considering its synthetic simplicity, showing MIC90 values ranging from 115,6 – 231,2 μM.
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Licochalcona H, Iodação-Regiosseletiva, Acoplamento de Suzuki, Bactérias, Micobactérias, Licochalcone H, Regioselective-Iodination, Suzuki coupling, Bacteria, Mycobacteria