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http://dx.doi.org/10.21577/0103-5053.20200053 J. Braz. Chem. Soc., Vol. 31, No. 8, 1668-1678, 2020 Printed in Brazil - ©2020 Sociedade Brasileira de Química Article New Diesters Derived from Piperine: in silico Study and Evaluation of Their Antimicrobial Potential Emmely O. Trindade,a Helivaldo D. S. Souza, a Maria Cláudia R. Brandão,b Hermes D. Neto, c Edeltrudes O. Lima,c Bruno F. Lira,a Petrônio F. de Athayde-Filhoa and José M. Barbosa-Filho *,c aDepartamento de Química, Universidade Federal da Paraíba, 58051-900 João Pessoa-PB, Brazil bInstituto Federal da Paraíba, Campus Areia, 58397-000 Areia-PB, Brazil cDepartamento de Ciências Farmacêuticas, Universidade Federal da Paraíba, 58051-900 João Pessoa-PB, Brazil Piperine, previously extracted from black pepper (Piper nigrum L.), was used as a precursor for the synthesis of twelve new diester derivatives. The final products were obtained through the bimolecular nucleophilic substitution reaction (SN2) of the alkyl 2-chloroacetates and the salt of piperic acid, obtained from the basic hydrolysis of piperine. The compounds were synthesized with yields of 55-84% and characterized by infrared spectroscopy and 1H and 13C nuclear magnetic resonance. The evaluation of the compounds’ potential as new drug candidates was done through an in silico study of ADME properties (absorption, distribution, metabolization and excretion) and evaluation of antimicrobial activity against bacterial strains (Staphylococcus aureus and Pseudomonas aeruginosa), yeasts (Candida albicans and Candida tropicalis) and filamentous fungi (Aspergillus fumigatus, Aspergillus flavus and Aspergillus niger). The in silico study showed that the compounds were good drug candidates and antimicrobial evaluation demonstrated that 9 of the 12 compounds exhibited a minimum inhibitory concentration (MIC) ranging 1024-256 μg mL−1. Keywords: piperine, diesters, antimicrobial activity Introduction and therapy costs are other factors that hinder adequate, successful and safe treatment against infectious agents. The number of drug-resistant microorganisms is Accordingly, the research and discovery of new, safe and increasing at alarming rates. The antibiotic resistance crisis effective antibiotics is of utmost importance to tackle the has been attributed to the overuse and misuse of these growing threat of infections caused by multidrug resistant medications, as well as a lack of new drug development microorganisms.3,5 by the pharmaceutical industry. When considering the Piperine (1-piperoyl-piperidine) is a natural amide with emergence of resistant strains, effective treatment of a molecular formula of C17H19NO3. It is a versatile bioactive fungal and bacterial infections has become increasingly compound found in almost 2000 species of the genus Piper, challenging for public health systems.1,2 Microorganisms being also the most abundant alkaloid present in black such as bacteria and fungi have the genetic ability to acquire pepper (Piper nigrum) and long pepper (P. longum).6,7 and transmit resistance to these drugs.3 Pathogenic agents Piperine alone has a broad spectrum of biological activities resist antimicrobial action through mechanisms such as: such as antiinflammatory, analgesic, anticonvulsant, reduction of the accessibility of the drug to its molecular antimicrobial, antioxidant, antitumor, antidepressant, target, decrease in cellular uptake and increase in drug hepatoprotective, antithyroid and immunomodulatory, efflux, resulting in a low and ineffective concentration among others.8,9 Its abundance in plant material, as well as of the drug, or even mutations that alter their molecular its ease of extraction and possible synthetic manipulations, targets, rendering the antibiotic useless.4 Besides, toxicity make piperine a rich source for the discovery of numerous derived molecules with promising biological potential. The *e-mail: [email protected] literature reports several activities of piperine derivatives, Vol. 31, No. 8, 2020 Trindade et al. 1669 such as antiinflammatory,10 antimicrobial,11 antineoplasic,12 was obtained with the following characteristics. Molecular antidiabetic,13 antichagasic14 and antivitiligo,15 among weight (MW) 285.34 g mol−1; mp 126-128 °C (lit.:15 −1 others. Thus, piperine derivatives have become notorious 129-130 °C); IR (ATR) ν / cm 3008 (C−HAr), 1631 (C=O), for its promising pharmacological activities, often superior 1581-1442 (C=CAr), 1249 (C−O−C); 930 oop (C−HAr); 1 to those of piperine itself. This in turn has led to an H NMR (400 MHz, CDCl3) d 7.40 (ddd, J 14.7, 8.9, 1.2 Hz, increased interest in the research and discovery of new 1H, CHolef), 6.95 (s, J 1.6 Hz, 1H, CHAr), 6.86 (dd, J 8.1, molecules derived from such natural compound. 1.7 Hz, 1H, CHAr), 6.76-6.66 (m, 3H, CHolef and CHAr), 6.41 Considering these aspects, twelve new diesters derived (d, J 14.6 Hz, 1H, CHolef), 5.94 (s, 2H, OCH2O), 3.60-3.48 from piperine were designed, synthesized and evaluated as (m, 4H, CH2cycloalk.), 1.64 (m, 2H, H-15, CH2cycloalk.), 1.59- 13 new drug candidates through in silico study and evaluation 1.53 (m, 4H, CH2cycloalk.); C NMR (101 MHz, CDCl3) d of in vitro antimicrobial activity. 165.5, 148.2, 148.1, 142.8, 138.4, 130.9, 125.3, 122.5, 119.7, 108.4, 105.6, 101.3, 46.3, 26.1, 24.6. Experimental Preparation of (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)penta- Chemistry 2,4-dienoic acid (piperic acid) (2) Piperine (1) was obtained by the extraction of black In a 50 mL flask, 2.20 g (7.72 mmol) of piperine and pepper (P. nigrum L.) with ethanol as described by Ikan16 in 22 mL of the ethanolic solution of 20% KOH were added. 1991. The other reagents and solvents were acquired from The reaction mixture was refluxed with stirring for 20 h. Sigma-Aldrich (São Paulo, Brazil) and used without further At the end of the reaction, the mixture was filtered, and the purification. The progress of the reactions was monitored by precipitate formed was washed with ethanol and dried. The thin layer chromatography (TLC) on silica gel plates. The precipitate was dissolved in water and acidified with 10% compounds were purified by recrystallization in ethanol HCl solution down to pH 3. The yellowish precipitate formed and the structures of compounds 6a-6l were confirmed was filtered out, washed with water, dried and recrystallized by the following: infrared spectroscopy (IR) spectra in ethanol.8 Piperic acid was obtained at 1.67 g (94.5% yield) obtained with a FTIR Shimadzu spectrometer, model with the following characteristics. MW 218.21 g mol−1; IR Prestige-21, with an attenuated total reflection (ATR) mp 217-218 °C (lit.:17 216-217 °C); IR (ATR) ν / cm−1 3448 1 13 accessory; H and C nuclear magnetic resonance (NMR) (O−H), 2922 (C−HAliph), 1676 (C=O), 1604-1419 (C=CAr), 1 spectra and two-dimensional (2D) NMR (correlation 1255 (C−O−C), 927 (C−HAr); H NMR (400 MHz, CDCl3) spectroscopy (COSY), heteronuclear single quantum d 12.20 (s, 1H, O−H), 7.36-7.26 (m, 1H, CHolef), 7.23 (s, 1H, correlation (HSQC) and heteronuclear multiple bond CHAr), 7.03-6.89 (m, 4H, CHAr and CHOlefin), 6.05 (s, 2H, 13 correlation (HMBC)) obtained with a Varian spectrometer, O−CH2−O), 5.93 (d, J 15.2 Hz, 1H, CHAr); C NMR 1 13 Mercury model (400 MHz for H and 101 MHz for C); (101 MHz, CDCl3) d 168.1, 148.5, 148.4, 145.1, 140.2, and melting point (mp) range on a MQAPF-3 heating plate. 130.9, 125.3, 123.5, 121.5, 108.4, 106.1, 101.8. Deuterated dimethyl sulfoxide (DMSO-d6) and deuterated chloroform (CDCl3) were used as solvents for dissolving Preparation of potassium piperate (3) the samples. The chemical shifts (d) were measured in parts per million (ppm) and the coupling constants (J) in An ethanolic solution of 10 mmol KOH was slowly hertz (Hz). added to a mixture of ethanol and piperic acid (10 mmol). The reaction mixture was stirred continuously at room Isolation of the amide 1-piperoyl-piperidine (piperine) (1) temperature for 1 h. The solid obtained was filtered and dried and had a yield of 93% and the following In a Soxhlet apparatus, 100 g of black pepper and characteristics. MW 256.30 g mol−1; IR (ATR) ν / cm−1 1000 mL of ethanol (95%) were added. The mixture was 3022 (C−HAr), 2908 (C−HAliph), 1550 (C=O), 1500-1448 refluxed for approximately 8 h. After concentrating the (C=CAr), 1255 (C−O). extract on a rotary evaporator, 100 mL of an alcoholic solution of 10% KOH were added, and the precipitated General procedure for obtaining alkyl 2-chloroacetates via material was then filtered out. A small amount of water was Fisher esterification 5a( -5h) added to the alcoholic solution until the mixture became turbid. After allowing the mixture to stand for 72 h, a yellow A mixture of 2-chloroacetic acid (20 mmol), the precipitate formed,16 and 3.5 g of piperine (3.5% yield) respective alcohol (4a-4h) (60 mL) and concentrated 1670 New Diesters Derived from Piperine J. Braz. Chem. Soc. sulfuric acid (1 mL) was refluxed for 6 h. Afterwards, Pentyl 2-chloroacetate (5g) the excess solvent was rotary-evaporated, and the residue MW 164.63 g mol−1; yield: 84%; IR (ATR) ν / cm−1 1753 poured into cold water. The residue was transferred to a (C=O), 1317, 1199 (C−O), 1172, 788 (C−Cl); 1H NMR separation funnel containing 250 mL of water, and 100 mL (400 MHz, CDCl3) d 4.17 (t, 2H, OCH2Aliph), 4.04 (s, 2H, of ethyl ether were then added. The organic phase was CH2Aliph), 1.70-1.59 (qt, 2H, CH2Aliph), 1.38-1.28 (m, 4H, 13 separated, washed repeatedly with 10% sodium bicarbonate CH2Aliph), 0.89 (t, 3H, CH3Aliph); C NMR (101 MHz, CDCl3) until neutral pH and then dried with anhydrous NaSO4.

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