Int J Pharm Pharm Sci, Vol 7, Issue 8, 105-109Original Article


SYNTHESIS OF QUINOLINYL-OXADIAZOLE AS A POTENT ANTIBACTERIAL AGENT AND SA-FABI INHIBITOR

DHANYA SUNIL*1, LAVEETA D’ALMEIDA1, SUVARNA G KINI2, RAMA M1

1*Department of Chemistry, Manipal Institute of Technology, Manipal University, Manipal 576104, India, 2Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal University, India
Email: dhanyadss3@gmail.com

Received: 24 Apr 2015 Revised and Accepted: 15 Jun 2015

ABSTRACT

Objective: Microbial resistance to currently marketed drugs is a serious problem worldwide and there is a vital need to develop novel antibiotics. Enoyl-ACP reductase (FabI) is essential for fatty acid biosynthesis and hence serves as an appealing target for antibacterials against methicillin resistant S. aureus. The present study focuses on the synthesis, antibacterial and saFab1 docking studies of three new series of quinoline derivatives: 5-[(quinolin-8-yloxy) methyl]-1,3,4-oxadiazole-2(3H)-thiones, N-(2,5-dimethyl-1H-pyrrol-1-yl)-2oxyacetamides and 2-(oxyacetyl)-5-methyl-2,4-dihydro-3H-pyrazol-3-ones with integrated ether linkages.

Methods: Three different substituted hydrazides were synthesized from substituted quinolinols. These hydrazides were allowed to undergo further reactions with carbon disulphide, 2,5-hexanedione and ethyl acetoacetate respectively to prepare 1,3,4-oxadiazole-2-thiones, N-substituted pyrrole acetamides and pyrazol-3-ones. The synthesized hydrazide derivatives were subjected to antimicrobial studies against Staphylococcus aureus. Docking studies were carried out using enoyl-ACP reductase crystal structure complexed with NADPH.

Results: 5-{[(2-methylquinolin-8-yl) oxy] methyl}-1, 3, 4-oxadiazole-2(3H)-thione (2b) with a methyl substituent on the quinoline ring was found to display significant antibacterial potential against S. aureus. Good binding interactions were observed in subsequent docking studies via formation of Fab1-NAD+-2b ternary complex through hydrogen bonding and stacking interactions.

Conclusion: 1, 3, 4-oxadiazole-2(3H)-thione (2b) was found to exhibit promising antibacterial potential against S. aureus.

Keywords: Oxadiazole, Antibacterial, saFab1, Triclosan.

INTRODUCTION

Antibiotics have turned the tide in terms of the treatment of various types of infectious diseases. But the evolution of antibiotic-resistant strains is of principally severe concern due to the biochemical fickleness of several bacteria and the over use of many of these antibiotics. Multidrug resistant bacteria have become a major public health crisis because existing antibiotics are no longer effective in many cases. Considering the rapid advance of multidrug resistance to the existing variety of marketed antibiotics, new approaches are immediately needed. In recent times very few novel antibiotics have been reported. Hence it is essential to discover antibiotics that act through the disruption of a novel target.

Staphylococcus aureus is a dangerous gram-positive pathogen that is readily transferred to immune-compromised patients [1, 2]. Methicillin-resistant S. aureus () strains are unfortunately widespread [3] and the well-recognized resistance among S. aureus strains against penicillins is apparently totally because of the production of an inducible β-lactamase. The severity of this problem has been further added by the fact that antibiotics that have usually been drugs of last resort like vancomycin are becoming the first line of treatment of resistant infections [4, 5]. Thus, there is an urgent requirement for newer antibiotics to combat these continually adapting pathogens.

One strategy that targets the bacterial cell envelope involves the selective inhibition of the type II fatty acid biosynthesis pathway (FAS II) which consists of individual mono functional enzymes that are responsible for the endogenous production of lipids to be incorporated into the bacterial cell membrane. The final reduction in this pathway is catalyzed by the NAD (P) H-dependant trans-2-enoyl- reductase (FabI), which plays a vital regulatory role. The S. aureus enoyl- reductase (saFabI) is the only known FabI which has a determinant role in completing cycles of elongation in type II fatty acid synthase systems with a clear preference for NADPH that has garnered the most attention as an antibacterial target. The clinical success of FabI inhibitors, such as isoniazid and triclosan validates this enzyme as a striking dug target [6, 7]. Triclosan binds at the FabI active site and the replacement of the ether linkage in triclosan by a carbon bridge prevents the formation of a stable FabI-NAD (P)1-drug ternary complex which is a key factor for the antibacterial activity of FabI inhibitors.

The oxadiazole group has been demonstrated to bear an important application in medicinal chemistry with anticancer, antiinflammatory, antituberculosis, antimalarial and anti schistosomiasis properties [8]. A number of therapeutic agents such as HIV integrase inhibitor raltagravir [9], nitrofuran antibacterial furamizole [10], a potent peptide deformylase inhibitor BB-83698 [11], antihypertensive agents tiodazosin [12] and nesapidil 13 are based on 1,3,4-oxadiazole moiety. Pyrrole derivatives represent a class of compounds of great importance in heterocyclic chemistry with biological importance [14, 15]. The presence of pyrazole moiety in organic molecules has proved to play ubiquitous role in the field of pharmaceutical chemistry [16-22]. In the present study, we explore few quinoline derivatives with an incorporated ether linkage for their antibacterial and Sa-FabI inhibitory potential.

MATERIALS AND METHODS

General

Thin layer chromatography was performed using pre coated aluminium sheets with Aluchrosep silica Gel 60/UV254 and spots were visualized in UV chamber. The elemental analysis of the newly synthesized compounds was carried out in Flash thermo 1112 series CHN analyser.

The IR spectra in KBr pellets and 1H-NMR and 13C-NMR spectra with TMS as internal standard and DMSO-d6 as solvent were recorded in a Schimadzu FTIR 8400S spectrophotometer and 400 MHz AV500 NMR spectrometer respectively. The mass spectrum was taken in a Schimadzu GCMS-QP5050 mass spectrometer. Melting points were determined by open capillary method and were uncorrected.

Synthesis

Three different substituted hydrazides were synthesized from substituted quinolinols by multistep reactions. Equimolar quantitities of substituted quinolinols and ethylchloroacetate was allowed to react in the presence of potassium carbonate for 18 h in dry acetone medium to give the ester. The ester obtained was further refluxed with hydrazine hydrate to give the corresponding hydrazides. The hydrazides were allowed to undergo further reactions to prepare 1, 3, 4-oxadiazole-2-thiones, N-substituted pyrrole acetamides and pyrazol-3-ones (Scheme-1).

Synthesis of 5-[(substitutedquinolin-8-yloxy) methyl]-1, 3, 4-oxadiazole-2(3H)-thiones [2a-c]

About 0.0038 mole of hydrazide was dissolved in a solution of 0.006 mol of KOH in 2 mL of water and 20 mL ethanol. To the above reaction mixture 2 mL carbon disulphide was added with stirring and refluxed for 8 h. Solvents were removed and the residue obtained was treated with water, filtered, dried and recrystallized from ethanol.

5-[(quinolin-8-yloxy) methyl]-1, 3, 4-oxadiazole-2(3H)-thione [2a]

Cream solid (53 %) m. p. 260 °C; Rf = 0.225; IR (KBr) [cm-1]: 3402 (N-H str.), 3055 (Ar. C-H str.), 1604 (C=N str.), 1180 (C=S str.), 1581 (Ar. C=C str.), 1257 (Ar. C-O-C asym. str.), 1103 (Ar. C-O-C sym. str.); 1H NMR [ppm] DMSO-d6, 400 MHz: 5.23 (s, 2H, OCH2), 7.31-8.21 (6H, Ar. H), 11.21 (brs, N-H); 13C NMR, 400 MHz, DMSO-d6 δ = 87.15, 114.90, 121.53, 123.72, 124.85, 128.24, 129.58, 135.67, 142.33, 142.24, 144.27, 155.20; MS (FAB+): m/z (%): 259 M+(100 %); Anal. Calcd. For C12H9N3O2S: C, 55.60; H, 3.47; N, 16.22; found: C, 55.78; H, 3.48; N, 16.27.

Scheme 1: Synthesis of compounds (2a-c), (3a-c) and (4a-c)

5-{[(2-methylquinolin-8-yl)oxy]methyl}-1,3,4-oxadiazole-2(3H)-thione [2b]

Cream solid (63 %) m. p. 264 °C; Rf = 0.61; IR (KBr) [cm-1]: 3456 (N-H str.), 3062 (Ar. C-H str.), 2916 (CH3 asym. str.), 2831 (CH3 sym. str.), 1612 (C=N str.), 1180 (C=S str.), 1573 (Ar. C=C str.), 1226 (Ar. C-O-C asym. str.), 1110 (Ar. C-O-C sym. str.); 1H NMR [ppm] DMSO-d6, 400 MHz: 2.66 (s, 3H, CH3), 5.24 (s, 2H, OCH2), 7.29-8.21 (5H, Ar. H), 11.21 (brs, N-H); 13C NMR, 400 MHz, DMSO-d6 δ = 20.03, 87.35, 115.29, 121.65, 122.94, 123.43, 128.24, 130.88, 136.50, 142.58, 144.67, 152.63, 153.29; MS (FAB+): m/z (%): 273 M+(100 %); Anal. Calcd. For C13H11N3O2S: C, 57.14; H, 4.03; N, 15.38; found: C, 57.35; H, 4.04; N, 15.41.

5-{[(5,7-dichloro-2-methylquinolin-8-yl)oxy]methyl}-1,3,4-oxadiazole-2(3H)-thione [2c]

Cream solid (66 %) m. p. 270 °C; Rf = 0.48; IR (KBr) [cm-1]: 3421 (N-H str.), 3139 (Ar. C-H str.), 1635 (C=N str.), 1184 (C=S str.), 1581 (Ar. C=C str.), 1218 (Ar. C-O-C asym. str.), 1103 (Ar. C-O-C sym. str.); 1H NMR [ppm] DMSO-d6, 400 MHz: 5.29 (s, 2H, OCH2), 7.45-8.29 (4H, Ar. H), 11.22 (brs, N-H); 13C NMR, 400 MHz, DMSO-d6 δ = 87.24, 121.93, 123.35, 129.03, 129.58, 130.43, 135.75, 138.18, 142.47, 144.25, 153.65, 154.28; MS (FAB+): m/z (%): 328 M+(100 %); Anal. Calcd. For C12H7N3O2SCl2: C, 43.90; H, 2.13; N, 12.80; found: C, 44.05; H, 2.14; N, 12.84.

Synthesis of N-(2,5-dimethyl-1H-pyrrol-1-yl)-2 substitutedoxy acetamides [3a-c]

About 0.0038 mol hydrazide in 10 ml ethanol was added to a mixture of 0.006 mol of acetonyl acetone and 1 mL glacial acetic acid. The reaction mixture was refluxed for 4 h, concentrated to half its volume and poured into 50 g crushed ice. Solid separated was filtered, washed with water and recrystallized from ethanol.

N-(2,5-dimethyl-1H-pyrrol-1-yl)-2-(8-quinolinoloxy)acetamide [3a]

White solid (66 %) m. p. 112 °C; Rf = 0.46; IR (KBr) [cm-1]: 3517 (N-H str.), 2916 (CH3 asym. str.), 2846 (CH3 sym. str.), 1689 (C=O str.), 1512 (Ar. C-C str.), 1249 (C-O-C asym. str.), 1118 (C-O-C sym. str.); 1H NMR [ppm] DMSO-d6, 400MHz: 1.95 (6H, CH3), 5.07 (s, 2H, OCH2), 5.63 (s, 2H, pyrrole), 7.31-8.89 (6H, Ar. H), 11.18 (s, N-H); 13C NMR, 400 MHz, DMSO-d6 δ = 19.96, 86.72, 93.90, 121.02, 123.14, 128.96, 129.35, 130.31, 132.55, 135.29, 138.20, 142.24, 153.38, 172.64; MS (FAB+): m/z (%): 295 M+(100 %); Anal. Calcd. For C17H17N3O2: C, 69.15; H, 5.76; N, 14.24; found: C, 69.40; H, 5.78; N, 14.28.

N-(2,5-dimethyl-1H-pyrrol-1-yl)-2-(2-methyl-8-quinolinoloxy) acetamide [3b]

White solid (72 %); m. p. 108-110 °C; Rf = 0.48; IR (KBr) [cm-1]: 3521 (N-H str.), 2908 (CH3 asym. str.), 2854 (CH3 sym. str.), 1695 (C=O str.), 1604 (Ar. C-C str.), 1257 (C-O-C asym. str.), 1106 (C-O-C sym. str.); 1H NMR [ppm] DMSO-d6, 400MHz: 1.94 (s, 6H, CH3), 2.61 (s, 3H, CH3), 5.09 (s, 2H, OCH2), 5.64 (s, 2H, pyrrole), 7.33-8.89 (5H, Ar. H), 11.19 (s, N-H); 13C NMR, 400 MHz, DMSO-d6 δ = 19.82, 20.09, 87.03, 93.81, 114.57, 121.51, 121.89, 123.35, 128.20, 128.22, 129.55, 132.62, 133.04, 137.50, 143.09, 172.73; MS (FAB+): m/z (%): 309 M+(100 %); Anal. Calcd. For C18H19N3O2: C, 69.90; H, 6.15; N, 13.59; found: C, 70.17; H, 6.16; N, 13.65.

N-(2,5-dimethyl-1H-pyrrol-1-yl)-2-(5,7-dichloro-8-quinolinoloxy) acetamide [3c]

Yellowish brown solid (62 %); m. p. 158-160 °C; Rf = 0.71; IR (KBr) [cm-1]: 3509 (N-H str.), 2931 (CH3 asym. str.), 2868 (CH3 sym. str.), 1766 (C=O str.), 1581 (Ar. C-C str.), 1266 (C-O-C asym. str.), 1103 (C-O-C sym. str.); 1H NMR [ppm] DMSO-d6, 400MHz: 1.95 (s, 6H, CH3), 5.09 (s, 2H, OCH2), 5.64 (s, 2H, pyrrole), 7.31-8.79 (4H, Ar. H), 11.21 (s, N-H); 13C NMR, 400 MHz, DMSO-d6 δ = 19.98, 87.12, 93.97, 121.82, 123.32, 129.05, 129.52, 130.44, 132.65, 135.71, 138.25, 142.37, 153.68, 172.75; MS (FAB+): m/z (%): 364 M+(100 %); Anal. Calcd. For C17H15N3O2Cl2: C, 56.04; H, 4.12; N, 11.54; found: C, 56.23; H, 4.13; N, 11.58.

Synthesis of 2-(substitutedoxyacetyl)-5-methyl-2,4-dihydro-3H-pyrazol-3-ones [4a-c]

About 0.0038 mol hydrazide was refluxed with 0.0038 mol of ethyl acetoacetate for 1 h with stirring. The resultant solution was allowed to cool to room temperature, washed thoroughly with ether to remove colored impurities, solid separated out was recrystallized from ethanol.

5-methyl-2-[(quinolin-8-yloxy)acetyl]-2,4-dihydro-3H-pyrazol-3-one [4a]

White solid (54 %); m. p. 156-158 °C; Rf = 0.5; IR (KBr) [cm-1]: 3155(Ar. C-H str.), 2977 (C-H asym. Str.), 2916 (C-H sym. str.), 1749, 1704 (C=O str.), 1242 (C-O-C asym. str.), 1118 (C-O-C sym. str.); 1H NMR [ppm] DMSO-d6, 400MHz: 1.85 (s, 3H, CH3), 5.10 (s, 2H, OCH2), 5.54 (s, 2H, pyrrole), 7.21-8.68 (6H, Ar. H); 13C NMR, 400 MHz, DMSO-d6) δ = 19.82, 46.00, 71.86, 117.76, 121.22, 125.1, 129.66, 130.78, 139.13, 142.02, 151.76, 155.5, 159.66, 172.70, 173.42; MS (FAB+): m/z (%): 283 M+(100 %); Anal. Calcd. For C15H13N3O3: C, 63.60; H, 4.59; N, 14.84; found: C, 63.84; H, 4.60; N, 14.89.

5-methyl-2-{[(2-methylquinolin-8-yl) oxy] acetyl}-2,4-dihydro-3H-pyrazol-3-one [4b]

Cream solid (84 %); m. p. 138-140 °C; Rf = 0.44; IR (KBr) [cm-1]: 3147 (Ar. C-H str.), 2977 (C-H asym. Str.), 2916 (C-H sym. str.), 1757, 1705 (C=O str.), 1250 (C-O-C asym. str.), 1119 (C-O-C sym. str.); 1H NMR [ppm] DMSO-d6, 400MHz: 1.86 (s, 3H, CH3), 2.33 (s, 3H, CH3), 5.12 (s, 2H, OCH2), 5.55 (s, 2H, pyrrole), 7.33-8.68 (5H, Ar. H); 13C NMR, 400 MHz, DMSO-d6 δ = 19.82, 27.36, 45.89, 71.66, 117.36, 121.12, 126.06, 129.68, 130.58, 139, 142.09, 155.5, 159.61, 163.06, 172.79, 173.36; MS (FAB+): m/z (%): 297 M+(100 %); Anal. Calcd. For C16H15N3O3: C, 60.61; H, 5.05; N, 14.14; found: C, 60.81; H, 5.06; N, 14.20.

2-{[(5,7-dichloroquinolin-8-yl)oxy]acetyl}-5-methyl-2,4-dihydro-3H-pyrazol-3-one [4c]

Cream solid (68 %); m. p.120-124 °C; Rf = 0.46; IR (KBr) [cm-1]: 3139 (Ar. C-H str.), 2985 (C-H asym. Str.), 2870 (C-H sym. str.), 1748, 1698 (C=O str.), 1296 (C-O-C asym. str.), 1103 (C-O-C sym. str.); 1H NMR [ppm] DMSO-d6, 400MHz: 1.86 (s, 3H, CH3), 5.18 (s, 2H, OCH2), 5.54 (s, 2H, pyrrole), 7.36-8.67 (4H, Ar. H); 13C NMR, 400 MHz, DMSO-d6) δ = 19.86, 46.09, 71.75, 125.17, 125.94, 128.34, 132.80, 133.26, 136.24, 142.02, 151.76, 156.29, 159.66, 172.7, 173.40; MS (FAB+): m/z (%): 352 M+(100 %); Anal. Calcd. For C15H11N3O3Cl2: C, 51.14; H, 3.13; N, 11.93; found: C, 51.25; H, 3.14; N, 11.96.

Antimicrobial studies

The antimicrobial activity of synthesized compounds was examined by Disc Diffusion Method. Nutrient agar media was prepared and plated on petriplates. Plates were inoculated by swab culturing using stock culture. Different discs were dipped in the solution of hydrazide derivatives and placed in inoculated plates using sterile forceps and were gently pressed. Plates were further incubated for 24 h at 37 °C for Gram+ve Staphylococcus aureus. The experiments were performed in duplicates. After incubation, diameter of an inhibition zone was measured. Tetracycline (500 µg/ml) was used as the standard drug.

Docking studies

The enoyl-ACP reductase crystal structure complexed with NADPH (Dihydro-Nicotinamide-Adenine-Dinucleotide Phosphate) with a corresponding entry code 4CUZ was recovered from the PDB database (www. pdb. org). Surflex dock module of sybyl ver 1.7 was used (Tripos Inc. St. Louis, USA) and protomol were generated based on already complexed ligand residues (i.e.1-(3-amino-2-methylbenzyl)-4-hexylpyridine-2(1H)-one) for carrying out docking studies. The proprietary software is licensed to Manipal Institute of Technology, Manipal University, India. The best favorable conformation in terms of highest docking score was chosen [23].

RESULTS AND DISCUSSION

The formation of cyclized product 5-[(substitutedquinolin-8-yloxy)methyl]-1,3,4-oxadiazole-2(3H)-thiones (2a-c) were confirmed by the IR absorption peaks observed at 1604 cm-1 and 1180 cm-1 due to C=N and C=S stretching vibrations. The 1HNMR spectra showed a singlet at 5.23 ppm corresponding to OCH2 protons and a broad peak at 11.21 ppm due to proton attached to nitrogen. The carbonyl stretch in the IR spectra of compounds 3a-c was observed at around 1690 cm-1.

The formation of pyrrole ring was confirmed by the singlet observed at 5.6 ppm in the 1HNMR spectra. The six identical protons of the methyl groups attached to the pyrrole ring were found to resonate at 1.9 ppm. The formation of pyrazol-3-ones was confirmed by the appearance of two carbonyl stretching vibrations in the IR spectra at 1700 cm-1 and 1750 cm-1. The 1HNMR spectra displayed the three methyl protons and the 2 protons in the pyrrole ring as singlets at 1.8 and 5.5 ppm respectively. The 13 C NMR spectra of all the synthesized compounds accounted for the respective number of carbon atoms. The mass spectra of the compounds were in agreement with the molecular weights of the compounds.

All the oxadiazole thione derivatives (2a-c) were found to show good antibacterial activity against S. aureus. The compound 2b with methyl substituent on the quinoline ring was found to be the most sensitive among the three oxadiazole thiones. Neither the pyrrole nor pyrazolone derivatives, exhibited any sensitivity towards the bacterial strain studied. The results of antimicrobial studies of the hydrazide derivatives expressed as mean value of the duplicates against S. aureus are given in table 1.

Table 1: Zone of inhibition and docking scores of quinoline derivatives

Comp. No. Zone of inhibitiona (mm) 4cuz(FabI)-docking score Comp. No. Zone of inhibition (mm) 4cuz(FabI)-docking score
2a 16 5.45 3c - 5.58
2b 20 6.67 4a - -
2c 11 6.34 4b - -
3a - 6.34 4c - -
3b - 6.58 Tetracycline 37 -

aInhibition zone expressed as mean of two replicas

The similarities in the structures of synthesized compounds and triclosan and its proposed mechanisms of action prompted us to determine whether the oxadiazoles were also FabI inhibitors. To investigate the suitability of saFabI as a drug target, we have structurally characterized this enzyme with respect to inhibitor binding and conformational flexibility and further compared with triclosan-saFabI complex structure. The results of the docking studies are presented in table 1. The docked conformer of 2b is depicted in fig. 1A. Triclosan is a particularly effective FabI inhibitor due to the slow formation of a stable, ternary FabI-NAD+-triclosan ternary complex, and this property of triclosan is responsible for its antibacterial activity through the formation of H-bond between oxygen attached to quinoline ring of 2b and NDP1258 of NADPH. The two nitrogen atoms of oxadiazole ring of 2b were also found to engage in H-bonds with Tyrosine 157 which is much similar to the sandwiched binding mode between triclosan, the protein and the cofactor. Hydrogen bond network and stacking interactions from the bridge that connects triclosan, protein and NAD+ [24]. Compound 2b also demonstrates the formation of ternary complexes with FabI. The ternary FabI-NAD+-2b complex formation is represented in fig. 1B.

Fig. 1: A) Docked conformer of 2b with the active residue of Fab1 and the substrate NADPH, B) FabI-NAD+-2b complex formation; Red-ligand, Green-Tyrosine 157 of Fab1 and Purple-NADPH

The ether linkage in tri closan is a structural feature that is essential for the formation of the inhibitory ternary complex. The substitution of a carbon bridge for the ether oxygen in triclosan results in a compound that cannot orient itself to optimally participate in this network. This is most likely attributed to the different angle of the carbon bridge compared with the ether bridge, preventing the molecule from forming hydrogen bond connections and the stacking interactions with NAD+ [25]. It is also proposed that the ether oxygen of triclosan is part of a hydrogen bond network that also includes the hydroxyl groups of Tyr-156, triclosan, and the NAD+ribose [26]. Thus, the presence of the ether oxygen is clearly important in promoting tight drug binding and the ensuing conformational change that leads to essentially irreversible FabI inhibition and potent antibacterial activity. Thus the presence of ether linkage and the ability to form ternary bonding might have made 2b the most potential antibacterial agent among all the compounds studied.

CONCLUSION

In the present study three new series of hydrazide derivatives incorporating bioactive quinoline moiety were synthesized and were characterized by spectral techniques. Antimicrobial activity of oxadiazole thione, pyrrole and pyrazolone derivatives of hydrazides was studied by disc diffusion method. All the oxadiazole thione derivatives showed good antibacterial activity against S. aureus.

Increased opportunities for hydrogen bond formation between the nitrogens and oxygen and the protein is one possible explanation for understanding the potency of 2b as a FabI inhibitor. Molecular modeling of the energy-minimized docked FabI-NAD1-2b structure indicated the formation of ternary bond formation. The ether linkage is an essential feature for ternary complex formation and ensuing conformational changes that can promote its interaction with FabI with potent antibacterial activity. Oxygen bridge in 2b which is critical to the formation of a ternary complex, similar to triclosan might have added to the structural features that determine inhibitory activity.

CONFLICT OF INTERESTS

Declared None

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