Plasmodium falciparum Histo-Aspartic Protease (HAP) inhibitor:  Toxicity Investigation and Docking Study of 2-(2-benzoyl-4-methylphenoxy)quinoline-3-carbaldehyde derivatives

doi:10.21203/rs.3.rs-2748975/v1

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Plasmodium falciparum Histo-Aspartic Protease (HAP) inhibitor: Toxicity Investigation and Docking Study of 2-(2-benzoyl-4-methylphenoxy)quinoline-3-carbaldehyde derivatives

https://doi.org/10.21203/rs.3.rs-2748975/v1

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Aspartic proteases possess catalytic sites for hydrolysis of peptide bonds which makes them potentials drug target in the malaria parasites. Inhibiting Histo-Aspartic Protease (HAP), aspartate (Asp₂₁₅) and histidine (His₃₂) residues of the P. falciparum disrupts the growth phase and ability to catalyse erythrocyte hemoglobin degradation. We synthesized compound 5; 2-(2-benzoyl-4-methylphenoxy)quinoline-3-carbaldehyde via Vilsmier-Hack and sp² C-H activation protocols. We then designed fifty hypothetical compounds A1-A50 which were screened in-silico for their toxicity, pharmacokinetics, bioactivity score and binding affinities. Nine lead compounds showed no toxicity to human cells. Ten standard antimalarial drugs were used as reference. The lead compounds were generally within (-0.28 to 0.32) as highly or moderately bioactive for six bioactivity score parameters. Compounds A31 had (-11.3 kcal/mol) and A5 (-11.2 kcal/mol) binding energies. Mefloquine with (-9.6 kcal/mole) was best reference drug coming in position 9. Whilst compound A31 and mefloquine both showed no interactions with either Asp₂₁₅ or His₃₂ in the binding pockets, compound A5 showed π-π stacking interactions. . We opine therefore, that based on other drug-likeness parameters investigated, compound A5; 2-(2-benzoyl-4-methylphenoxy)-7-methylquinoline-3-carbaldehyde can be recommended as a possible candidate for new antimalarial drug development in line with SDG goal 3 on health and well-being.

Medicinal Chemistry

Organic Chemistry

Malaria

Mefloquine

Binding energy

Drug leads

Oral bioactivity score

Pharmacokinetics

Malaria remains an important infectious disease characterized by acute febrile illness. According to WHO, the global estimated burden is between 200 – 300 million with about 627,000 deaths in the year 2020 [1]. Among all the Plasmodium species causing malaria, Plasmodium falciparum is the most dreadful and prevalent in Africa [2]. Over the past two decades, drug-resistant strains of P. falciparum have emerged to a distressing state, whilst also observing a reduction in efficacy of currently available drugs. These pervasive challenges have motivated the search for novel drugs, or redesigning of existing chemical compounds as part of a more viable treatment protocol to engender a sustainable global public health.

An emerging approach to overcome drug-resistance shown by a disease pathogen such as the malaria parasite is to explore another biological component different from the traditional target sites. Plasmepsins, the aspartic proteinase that are present in the malaria parasites have become promising drug targets for malaria treatment [3]. Histo-Aspartic Protease (HAP) is one of the four plasmepsins that resides in the food vacuole of the P. falciparum [4]. During growth phase of the Plasmodium, the parasite uses the HAP to catalyze the degradation of the erythrocyte hemoglobin at peptide bonds (known to be cleavage sites in the degradation pathway) to obtain amino acids for its protein nutrient enrichment [5], whereas, other plasmepsins are involved in other functions [6].

Intuitively, by taking cognizance of the aspartate (Asp₂₁₅) and histidine (His32) residues within the active site of HAP, and the high affinity for aspartic protease inhibitor Pepstatin-A, may present a viable strategy to block the sites functionality thereby inhibiting the protease of the Plasmodium parasite [7]. Thus, knocking out the HAP’s hemoglobin degrading ability could reduce propagation of the parasite in the host cells whilst preserving the hemoglobin of the infected erythrocytes.

Quinoline is one of the important organic compounds that occur in some natural compounds especially alkaloids and pharmacologically active substances. Derivatives of quinoline moiety have been reported to inhibit proteases of Plasmodium in vitro and in vivo [8]. The quinoline moiety occurs in some current standard drugs shown in Figure 1, similarly in compounds (Figure 2), for example which are used in the treatment of conditions such as; antibacterial, anthelmintic, anticancer, antifungal, antihypertensive, anti-inflammatory, analgesic, antiviral properties [9-14].

There is a dearth of information on drug targeted design of quinoline derivatives as HAP inhibitors. Hence, we evaluated in-silico relative binding affinity of some hypothetical quinoline derivatives with the Histo-Aspartic Protease (HAP) of P. falciparum. We chose HAP because of its availability as a divergent vacuolar plasmepsin, with no similarity in any known species of Plasmodium [15, 16]. Thus, we prepared 2-(2-benzoyl-4-methylphenoxy)quinoline-3-carbaldehyde (Scheme 1, Figure 3a-c), and evaluated its in-silico toxicity which returned as mildly carcinogenic (Table 1a). Thereafter, fifty hypothetical derivative compounds were designed (Figure 4) for in-silico screening to identify lead antimalarial candidates based on: absorption, distribution, metabolism, excretion and toxicity (ADMET) tests.

We further investigated their pharmacokinetics, bioactivity scores and molecular docking into the binding pockets of the histo-aspartic protease of Plasmodium falciparum. This drug-design protocol provides insights on the HAP enzyme active sites amino acid residues binding interactions with the ligand compound, which is quite significant in the development of desirable drug-likable candidate inhibitors.

2.1 Synthesis of 2-(2-benzoyl-4-methylphenoxy)quinoline-3-carbaldehyde (5)

Phosphorous oxychloride, POCl₃ (28 ml) was added dropwise at 0 ^oC in an ice bath to dimethylformamide, DMF and an orange colour change was observed. This mixture was then added to acetanilide (10 g, 1 equiv.) dissolved in DMF (30 ml). The reaction temperature was increased from 0 to 80 ^oC for 9 hours while monitoring with TLC. At completion, the reaction mixture was allowed to cool and thereafter in dropwise was poured into a stirring ice bath over 30 minutes. The precipitate obtained was washed with distilled water (50 ml x 5) to remove any remaining acid. The precipitate was filtered and air-dried over 48 hours.

To a mixture of p-Cresol (1.70 ml, 10.44 mmol) and K₂CO₃ (4.33 g; 31.32 mmol) in DMF (15 ml) was added the precipitate; 2-chloroquinoline-3-carbaldehyde 2 (2.00 g, 10.44 mmol). The reaction mixture was stirred at 90 ^oC for 9 hours. At completion, water (15 ml x 3) was added to the reaction mixture and the solid obtained was filtered before recrystallisation from ethylacetate (10 ml) to afford white solid, 2-phenoxyquinoline-3-carbaldehyde 4 used as precursor for the benzoylation reaction.

In step 3, to a mixture of 2-phenoxychloroquinoline-3-carbaldehyde 4 (0.10 g; 0.38 mmol; 1.0 eqv.) placed in an oven-dried reaction tube was added (NH₄)₂S₂O₈ (0.24 g; 2.0 eqv.), Ag₂O (1.0 eqv.) as co-oxidant and Pd(OAc)₂ (0.008 g; 0.04 mmol; 0.1 eqv.) as catalyst. The mixture was flushed with nitrogen to evacuate air. Dichloroethane (2 ml) was added to the reaction and stoppered. The mixture was stirred at 100 ^oC for 12 hours and monitored with TLC. After completion, ethylacetate (20 ml x 3) was used for extraction. The organic layer was washed with water (15 ml x 3), and dried with anhydrous sodium sulphate, filtered and concentrated under vacuum. The residue obtained was purified through column chromatography on silica gel (60-120 mesh) using hexane: ethylacetate (1:19) to give compound 5; (2-phenoxyquinoline-3-carbaldehyde) in 60% yield. The product was characterized by FTIR, ¹H NMR and HRMS.

2.2 Toxicity Prediction of compound (5)

Toxicity tests of synthesized compound 5 was carried out by uploading its SMILES (drawn with Chem draw 14.0, saved as mol file in .sdf format) into Protox II webserver (https://tox-new.charite.de/protox_II/). The hepatoxicity, carcinogenicity, immunotoxicity, mutagenicity and cytotoxicity data generated were extracted [17].

2.3 Preparation of its hypothetical compounds (A1-A50) and Antimalarial reference drugs

Fifty (50) hypothetical compounds were conceptualized and drawn using Chemdraw 14.0, saved in .sdf format and their SMILES uploaded into Protox II webserver (https://tox-new.charite.de/protox_II/) Figure 6. Ten antimalarial drugs; artesunate, doxycycline, tafenoquine, amodiaquine, artemeter, lumefantrine, primaquine, piperaquine, mefloquine and chloroquine were obtained from Pubchem (https://pubchem.ncbi.nlm.nih.gov/) for comparison. The downloaded structures were also saved in .sdf format and their smiles uploaded into Protox II webserver (https://pubchem.ncbi.nlm.nih.gov/) for virtual screening to investigate their toxicity and compliance to all drug-likeness rules [18].

2.4. Selection of Histo-Aspartic Protease (HAP) protein receptor

The crystal structure of Histo-Aspartic Protease (HAP) protein molecule with resolution of 2.10 Å was obtained from the protein data bank at rcsb.org (https://www.rcsb.org/) in pdb format and prepared using BIOVIA Discovery Studio DS 2020 to remove unwanted ligands and water molecules. Polar hydrogen atoms were added accordingly.

2.5 In-silico drug-likeness and ADME predictions

Drug-likeness analysis of compounds A1-A50 were undertaken using admetSAR2 (http://lmmd.ecust.edu.cn/admetsar2) to predict adsorption, distribution, metabolism and excretion (ADME) parameters for drug leads [19]. The smiles were loaded into webserver and result generated were extracted and analysed.

2.6. Bioactivity score

Bioactivity score such as G-protein-coupled receptors (GPCR) ligand, ion channel modulator (ICM), kinase inhibitor (KI), nuclear receptor ligand (NRL), protease inhibitor (PI) and enzyme inhibitor EI) of the lead compounds identified were evaluated using the online Molinspiration drug-likeness score at (www.molinspiration.com). This was done by loading the smiles of the lead compounds into the web server. The values obtained were plotted using excel [20].

2.7 Molecular docking study

Investigation of the inhibitory ability of synthesized compound 5, and selectedhypothetical compounds were carried out against histo-aspartic protease (HAP) using docking simulations performed with by PyRx 0.8 AutoDock Vina Wizard before converting to Autodock macromolecules. Flexible ligand to rigid protein procedure were followed and all potential binding sites on the target protein were utilised. Docking was done within 90 × 75 × 60 cubic grid-centered on the protein and enclosing the entire protein which lasted for about one hour. A grid spacing of 1.00 Å was used for the calculation of the grid maps using the autogrid module of Auto-dock tools using a set of nine (9) independent runs for each ligand.

The potential binding sites identified influences the selected energetically favorable binding conformations using AutodockVina [21]. The mode, binding affinity of the modes and RSB (upper and lower) values were obtained as guides to the highest binding score for each ligand. The mode with the best binding affinity is selected. Analysis of the ligand-protein complex was done using DS visualizer. All software’s were run on PC-based machines running Microsoft windows 10 operating systems.

3.1 Synthesis of 2-(2-benzoyl-4-methylphenoxy)quinoline-3-carbaldehyde (5) and preparation of hypothetical compounds (A1-A50) as ligands

The compound 5; 2-(2-benzoyl-4-methylphenoxy)quinoline-3-carbaldehyde was obtained as shown in Scheme 1, and characterized using FTIR, HRMS and 1H-NMR (Figure 3a-c). We investigated drug-likeness for compound 5 which showed mild carcinogenicity (Table 1). In order to identify candidates with better drug-likeness, fifty hypothetical compounds were designed based on structural modifications with substituents in positions 4-, 5-, 6-, 7-, and 8- of the quinoline core, meta position of the methylphenoxy group and para position of the benzoyl group (Figure 4).

3.1.1 Structural elucidation of Compound (5)

White solid; reaction time: 12 h; yield: 60 %; m.pt: 119-121 °C; IR (neat) v max (cm^-1) 3057, 2922, 2856, 2739, 1754, 1690, 1612, 1590, 1494, 1461, 1343, 1257, 1199, 1097, 760; ¹H NMR (400 MHz, CDCl₃) δ 9.75 (s, 1H), 8.32 (s, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.80 (t, J = 8.2 Hz, 1H), 7.74 (t, J = 7.5 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.51 (d, 1H), 7.39 (t, 1H), 7.19 (s, 1H), 6.86 (d, 1H), 6.84 (d, 1H), 2.41 (s, 3H). HRMS (ESI): Calc. for [(C₂₄H₁₇NO₃)](M+H)⁺ 368.1281, found 368.1283.

3.2 Toxicity results of compound (5), hypothetical compounds (A1-A50) and ten Antimalarial Reference drugs

All fifty hypothetical compounds (A1-A50) in Figure 4 and ten reference drugs; artesunate, doxycycline, tafenoquine, amodiaquine, artemeter, lumefantrine, primaquine piperaquine, mefloquine and chloroquine were virtually investigated for their toxicity profiles; hepatoxicity, carcinogenicity, immunogenicity, mutagenicity and cytotoxicity as given on Table 1a. Noticeably, while compound 5 and forty-one of the hypothetical derivatives failed one or more of those tests suggesting possible toxic and carcinogenic activities [22], however nine (9) lead compounds A5, A20, A31, A33, A34, A36, A45, A48 and A49 (Figure 5) were fully compliant (Table 1a and b).

Interestingly, results of toxicity for the reference drugs as presented in Table 2a-b returned only mefloquine as compliant, while others had one or more violations in comparison with the nine lead compounds. Mefloquine was therefore selected for further virtual study along with the selected lead compounds.

3.3 In-silico drug-likeness and ADME predictions

Our results in Table 3 shows that the lead compounds have hydrogen bond donors (nitrogen–hydrogen and oxygen–hydrogen bonds (0 – 1), and (<5), while the hydrogen bond acceptors (all nitrogen or oxygen atoms) (4 - 7) also (<10), are in compliance to the rule of five (RO5) [18]. Their molecular weights range (367.40 to 449.40 g/mol) which also fits the (150 to 500 g/mol) rule. The TPSA observed were (56.26 to 104 Å²) which falls within the range (20 to 130Å²)rule. Number of rotatable bonds were not more than 9.

Compounds A20, A45 and A49 were less permeant than others as revealed by their higher negative log Kp values (-5.13 to -5.18) [23]. Unlike others, compounds A31, A36 and A45 showed low gastrointestinal absorption values. This could be attributed to presence of the trifluoromethyl group at position 6 of compound A31, the thiol group at position 8 of compound A36, and both methoxy at position 6 and thiol at position 3 of the methylphenoxyl ring. Interestingly, compound 5 is blood brain barrier permeant unlike all the lead compounds. While compounds A31, A33, A34 and A36 are P-glycoprotein (P-gp) substrates [23, 24].

Six of the nine derivatives in addition to compound 5 exhibited high gastro-intestinal absorption except A31, A36 and A45. Furthermore, unlike all the other lead, compound 5 can penetrate the blood brain barrier (BBB) (Table 3). The nine lead compounds all have good oral bioavailability of 0.55, although with one allowable violation [18]. Inhibition of cytochromes P450 isoenzymes has been linked to the major cause of pharmacokinetics-related drug-drug interactions which could lead to toxic or adverse effects when there is lower clearance, accumulation of drug or metabolites. Table 4 reveals that the lead compounds are CYP2C19 inhibitors, while being substrates to CYP2D6. These cytochromes are involved in the metabolism and elimination of approximately 25% of clinically used drugs involved in the addition or removal of certain functionalities through; hydroxylation, demethylation and dealkylation [25].

3.4 Bioactivity score

The probability of drug leads as potential candidate can be evaluated using their bioactivity scores.

In Figure 6 all the lead compounds generally fall within highly or moderate bioactivity for all the parameters. Specifically, compounds A20 and A48 are highly active for five of the six parameters with bioactivity scores from 0.00 to 0.33. Compounds A5 and A31 have high bioactivity as kinase inhibitor (0.23 and 0.22) with capacity to block cancer cells [26], as nuclear receptor ligands (0.18 and 0.26) for hydrophobic molecules such as fatty acids, cholesterol and lipophilic hormones [27], as glycoprotein receptors GPCR (0.07 and 0.08) which regulate metabolic enzymes, or promoter proteins etc. [28], while A5 is also an enzyme inhibitor with value of 0.1 being able to bind to other available sites on the enzyme [29]. The compound with lowest bioactivity score is A36. All the lead compounds are only moderately active as protease inhibitor with values of (-0.18 to -0.28) implying having the capacity to prevent new HIV cells from becoming mature virus [30]. Only compounds A20 and A48 are highly active as ion channel modulators with values of (0.04 and 0.07) respectively which are above 0.00 [31].

3.5 Molecular docking study

Results from the docking of ligands and reference drugs against HAP is presented in Table 5. The binding energy for compound A31 (-11.3 kcal/mole) and compound A5 (-11.2 kcal/mole) are higher than compound 5 (-10.9 kcal/mol). Additionally, the next six of the lead compounds have binding energies of (-10.8 to -9.8 kcal/mole) all higher than the ten reference drugs investigated, for which the best performing mefloquine had -9.6 kcal/mole while the lowest was chloroquine with -6.0 kcal/mole.

The 3-D structure of P. falciparum histo-aspartic protease (PDB ID: 3QVC) and its hydrogen acceptor/ donor surface interaction with compound A31 is shown in Figure 7a. We observed in the 2-D view, Figure 7b, hydrogen binding interaction of the carbaldehyde oxygen atom of the quinoline core with Phe₁₀₉ at bond length 3.51 Å. Also strong fluorine bonds of the trifluoromethyl groups at position 7 with Glu₈₆, Arg₉₁, Lys₇ and Ala₁₀ (bond lengths ranging from 2.98 to 3.58 Å) may presumably be responsible for the high inhibitory interactions of 2-(2-benzoyl-4-methylphenoxy)-8-methyl-6-(trifluoromethyl)quinoline-3-carbaldehyde (A31) with Plasmodium falciparum (HAP). Other bonds contributing to the interaction as presented in Figure 7b are alkyl, π-π alkyl, π-π stacked and π alkyl at various bond lengths with the residues of the protein.

Hydrophobic interactions (Figure 7c) are highly crucial for the folding of proteins especially in keeping the protein stable and biologically active through decrease in surface area thereby reducing the undesirable interactions with water [32]. Herein, compound A31 exhibits hydrophobic interactions with the P.falciparum HAP amino acid residues especially the 2-benzoyl-4-methylphenoxy side of the molecule interacting with Leu₇₃, Ile₈₀, Tyr₁₁₂, Phe₁₁₁, Trp₃₉ and Ile₁₀₇.

Interaction with the trifluoromethyl side of the quinoline molecule with Glu₈₆, Arg₉₁, Lys₇ and Ala₁₀ clearly appears to be hydrophilic due to the electronegative character of fluorine atom as shown in Figure 7c. Solvent accessibility (SAS) is a key feature of proteins for determining the folding and stability of a molecule [33]. In Figure 7c, the solvent accessibility surface, blue region in the 3D interaction is large thereby suggesting better interaction of compound A31 with the binding pocket of the HAP protein.

Similarly, the 3-D structure for compound A5 is shown in Figure 8a with binding energy of -11.2 kcal/mol. The absence of hydrogen bond does not reduce its efficacy as HAP inhibitor due to other interactions such as π-cation (pi electrons of the quinoline core and the amino hydrogen of the side chain of Lys₇), alkyl and π-alkyl (ligand and amino acid residues such as Val₁₂₀, Leu₇₃, Tyr₄₁₀, Leu₇₃, Ile₈₀, Ile₁₀₇ and Pro₁₁₀), π-π stacked and π-π T-shaped (compound A5 and Phe₁₁₁, Phe₁₀₉, His₃₂ and Trp₃₉) all contributed to its high binding energy (Figure 8b).

We observed in Figure 8c that compound A5 displays significant hydrophobic interaction with all observed binding residues except Lys₇, to suggest good water-lipid interface transport between cell membrane of Pf HAP protein. Furthermore, the quinoline core of compound A5 is exposed to better solvent accessability to imply a more open conformation predisposed to easier interaction with the reactive sites of the target residues [34].

The binding interactions of the best reference drug Mefloquine with P. falciparum histo-aspartic protease residues (Figure 9a) showed that the trifluoro groups attached to position 6 in compound A31 and position 8 in Mefloquine both appear to contribute to their increased activity. However, unlike compound A31, Mefloquine does not have any hydrogen bonding which could have explained its lower binding energy.

Similarly, solvent accessibility surface interaction of compound A31 is higher for Mefloquine suggesting better interaction in the binding pocket of the HAP protein.

In this study, through toxicity profile tests, we have evaluated a synthesized compound 5 and its fifty hypothetical compounds A1-A50 for their drug-likeness using virtual tools to identify lead drug candidates to address resistance to current reference antimalarial drugs. Nine hypothetical compounds showed no toxicity to human cells. Compounds A5 and A31 have high bioactivity as kinase inhibitor, as nuclear receptor ligands, and as glycoprotein receptors GPCR. Additionally, compound A5 is an enzyme inhibitor being able to bind to other available sites on the HAP enzyme.

We join others to hypothesise that since aspartate (Asp₂₁₅) and histidine (His₃₂) residues in the active site of HAP are desirable for the parasite growth, and particularly contribute to its virulence, thus ligand interaction at this location will serve as a good inhibitor in a drug-development protocol.

Herein, while compound A31 with binding energy -11.3 kcal/mole does not show evidence of interaction with either Asp₂₁₅ or His₃₂, however compound A5 with binding energy -11.2 kcal/mole has π-π stacking interactions with His₃₂. Mefloquine the best performing reference drug also does not show any interaction with either of Asp₂₁₅ or His₃₂. Furthermore, compound A5 was observed to show significant hydrophobic interaction with all observed binding residues except Lys₇, to suggest good water-lipid interface transport between cell membrane of Pf HAP protein and also exposure of the quinoline core to better solvent accessability which pressuposes that the conformation is more open enabling better binding with the reactive sites of the target residues. Our study shows that compound A5 may be considered in a new drug development protocol for antimalarial disease.

Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Funding Information

This work was funded, in parts, by the University of Lagos Central Research Committee (CRC No. 2015/25), Nigerian Government TetFund IBR (CRC/TETFUND/No. 2018/016)

Author Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Olufemi Aina and Bello Adebayo. The first draft of the manuscript was written by Luqman Adams and Oluwole B. Familoni and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Scheme 1 is available in the Supplementary Files section.

Tables 1 to 5 are available in the Supplementary Files section

Scheme1.png
Scheme 1: Synthesis of 2-(2-benzoyl-4-methylphenoxy)quinoline-3-carbaldehyde (5)
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Plasmodium falciparum Histo-Aspartic Protease (HAP) inhibitor: Toxicity Investigation and Docking Study of 2-(2-benzoyl-4-methylphenoxy)quinoline-3-carbaldehyde derivatives

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