Original Article revista.iq.unesp.br | Vol. 47 | n. 4 | 2022 | 27 Eclética Química Journal, vol. 47, n. 4, 2022, 27-36 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.4.2022.p27-36 Biological evaluation of selected metronidazole derivatives as anti-nitroreductase via in silico approach Moriam Dasola Adeoye1 , Abel Kolawole Oyebamiji2+ , Mojeed Ayoola Ashiru1 , Rasheed Adewale Adigun1 , Olabisi Hadijat Olalere1 , Banjo Semire3 1. Fountain University, Faculty of Science, Osogbo, Osun State, Nigeria. 2. Bowen University, Department of Chemistry and Industrial Chemistry, Iwo, Nigeria. 3. Ladoke Akintola University of Technology, Faculty of Pure and Applied Science, Ogbomoso, Nigeria. +Corresponding author: Abel Kolawole Oyebamiji, Phone: +2348032493676, Email address: abeloyebamiji@gmail.com ARTICLE INFO Article history: Received: February 27, 2022 Accepted: July 11, 2022 Published: October 28, 2022 Keywords: 1. ligand 2. antibacterial 3. gastric 4. phytochemicals 5. ADME Section Editors: Assis Vicente Benedetti ABSTRACT: The 1-(2-hydroxyethyl)-2-methyl-5- nitroimidazole (2HMN) is a powerful antibacterial and antiparasitic drug used alongside other drugs against Helicobacter pylori infection and was investigated the effects of substituents: –OH (A), H (B), –SPh (C), –COOH (D), –NO2 (E) and –OCH3 (F) on the interactions of 2HMN with the target nitroreductase Rdxa protein for the treatment of the infection. Spartan 14 (optimization), PyMOL 1.7.4.4 (to treat downloaded protein), Autodock Tool (locate protein binding site), Autodock vina 1.1.2 (docking calculation) were used to discover the nonbonding interaction between docked complexes using SWISSADME and Pre-ADMET software. The band gaps order for the studied compounds were C < A < F < B < D < E, a probability of highest charge distribution and activity for SPh substituted derivatives and the ligands conformed to the Lipinski’s rule of five. Compounds D and E are noninhibitors and nonsubstrate for cytochrome P450 2C9, P450 2D6, P450 2C19 with the same efficient calculated binding affinity (–21.3 kJ mol–1) and inhibition constant (7.8) comparable to the standard compound A. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.4.2022.p27-36 mailto:abeloyebamiji@gmail.com https://orcid.org/0000-0002-1274-9452 https://orcid.org/0000-0002-8932-6327 https://orcid.org/0000-0002-6742-4698 https://orcid.org/0000-0002-9588-4966 https://orcid.org/0000-0001-6885-0253 https://orcid.org/0000-0002-4173-9165 Original Article revista.iq.unesp.br 28 Eclética Química Journal, vol. 47, n. 4, 2022, 27-36 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.4.2022.p27-36 1. Introduction Helicobacter pylori (H. pylori), a microaerophilic gram-negative bacterium, has been described as the first formally recognized carcinogenic bacterial, and one of the most successful human pathogens which is believed to be transmitted from person to person through closed contact and exposure to fecal matters or vomit (Fig. 1) (Bürgers et al., 2008; Kayali et al., 2018). These bacteria are typically found in the mucous layer that covers and protects the stomach and small intestine’s tissues (Houghton and Wang, 2005). Its infection, by inflaming the stomach’s inner layer, which is a complicated interplay between the bacterial, the host, and environmental factors, has been established to be the key factor with various gastric diseases such as chronic gastritis, peptic ulcers, and gastric mucosa-associated lymphoid tissue (MALT) lymphoma (Jemilohun and Otegbayo, 2016; Wu et al., 2009). Although, many other factors, such as the persistent use of anti-inflammatory pain relievers, including aspirin, are responsible for peptic ulcer diseases (Bürgers et al., 2008). The clinical use of many 5-nitroimidazoles derivatives, especially metronidazole [1-(2- hydroxyethyl)-2-methyl-5-nitroimidazole] (2HMN) as antibiotic for the effective treatment of patients with H. pylori linked gastritis and peptic ulcer ailment, has been listed and approved by the World Health Organization. Metronidazole (A) (Fig. 2) has also been used in combination with other antibiotics such as tetracycline, amoxicillin and clarithromycin to treat ulcer. However, it is uncommon to find both bacteria and protozoa to cause ulcer (Houghton and Wang, 2005). Some studies (Ghotaslou et al., 2015; Kim et al., 2020) in the last few years have reported that H. pylori is exhibiting an increasing double resistance to metronidazole and this has drawn the attention many researchers to study physiological and pharmacological significance of some metronidazole and its derivatives (Alawadi et al., 2015). To contribute to this ongoing area of research, this study investigates the relative substituents’ effects on the interactions of some nitroimidazole derivatives on the target; nitroreductase Rdxa proteins (PDB ID: 3qdl). The roles of computational chemistry for the qualitative and quantitative evaluation of substances and in almost every field of chemistry cannot be overstated. Of recent, it is routinely used to accelerate the long and costly drug discovery/design activities, from drug target identification, commonly a receptor or an enzyme, to the design and optimization of new drug-like compounds. Thus, each computational chemistry method can impact and accelerate a given phase of the drug discovery process, from structure-based drug design technique molecular docking (stimulation of molecular interaction and generation of potent inhibitory ability, i.e., binding affinity), molecular dynamics for hit identification and lead generation to quantitative structure-activity relationship (QSAR) (Adejoro et al., 2016). The quantum mechanically derived molecular descriptors and physicochemical variables also dictate the pharmacokinetics of any studied compounds (Venkatesh and Aravinda, 2017). These calculated descriptors affect their drug-likeness and, ultimately, their absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, which are the key factors to be optimized to generate drug candidate in clinical trials (Palermo and Vivo, 2015). ADMET properties influence the drug levels and the kinetics of drug exposures to the tissues, and, hence, the performance and pharmacological activities of compounds as drugs (Patil, 2016). This study, therefore, determines the ADME properties of the studied 2HMN and some other derivatives of nitroimidazole to investigate their oral- bioavailability and drug-likeness properties. Figure 1. Pictorial view of H. pylori. Source: Bürgers et al. (2008). Figure 2. Structure of metronidazole [A]. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.4.2022.p27-36 Original Article revista.iq.unesp.br 29 Eclética Química Journal, vol. 47, n. 4, 2022, 27-36 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.4.2022.p27-36 2. Materials and Methods 2.1 Ligand Preparation The ligands preparation and computational analyses of the studied compounds were carried out with Spartan- 14 software package at DFT/B3LYP/6-311G** level of theory. Using molecular editor builder of Spartan 14, the equilibrium geometries of each of these compound A–F (Tab. 1), were modeled, and their structures were minimized. The compounds were fully optimized (Fig. 3) using equilibrium geometry at ground state, with the features in the personal computer Spartan 14 software at HF-DFT self-consistent field level of theory, to estimate the physicochemical properties; dipole moment, polarizability, solvation energy, partition coefficient (log P), a measure of lipophilicity/ hydrophobicity, frontier orbital energies (EHOMO and ELUMO) of the studied compounds. Following their geometry optimization, their energy gaps (EHOMO–ELUMO) were computed. The EHOMO and ELUMO of the modeled molecules were related to the ionization potential (IP), the electron affinity (EA), and the global hardness (η), using Koopman’s theorem (1–3) (Adeoye et al., 2019). These descriptors help to predict, on theoretical basis, the chemical activities of these compounds. Figure 3. Structures of (a) [raw protein (3dql)] and (b) [cleaned protein]. Source: Martínez-Júlvez et al. (2012). Table 1. Two-dimensional (2D) structures of the studied compounds. R1 Name A OH 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole B H N-ethyl-2-methyl-5-nitroimidazole C SPh 1-(2-thiophenylethyl)-2-methyl-5-nitroimidazole D COOH 1-(2-carboxylethyl)-2-methyl-5-nitroimidazole E NO2 1-(2-nitroethyl)-2-methyl-5-nitroimidazole F OCH3 1-(2-methoxylethyl)-2-methyl-5-nitroimidazole 2.2 Preparation of the Studied Receptor (Protein) The target protein for this study was nitroreductase Rdxa protein (PDB ID: 3QDL) (Martínez-Júlvez et al., 2012). The 3D structure (X-ray diffraction) was obtained from the protein data bank and treated with PyMOL 1.7.4.4 for the removal of water molecules and any other residues apart from the desired molecule. Schrödinger (Maestro 12.7) (Morakinyo et al., 2022) and the https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.4.2022.p27-36 Original Article revista.iq.unesp.br 30 Eclética Química Journal, vol. 47, n. 4, 2022, 27-36 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.4.2022.p27-36 references therein attached journals were used to determine the target protein’s active site, in preparation for site specific docking. The structure of the raw protein (3dql) from the data bank and the cleaned protein are as presented in Figs. 4a and b. 2.3 Molecular Docking Analysis The optimized compounds were docked into the active pockets of the target H. pylori protease; nitroreductase Rdxa protein (PDB ID: 3QDL), using two softwares with different algorithm profiles (Autodock Vina and Discovery studio) to predict their binding abilities with the studied receptor (Forli et al., 2016; Roche et al., 2015). The docking process mainly involves spatial matching and energy matching (Meng et al., 2011) between the ligand and the receptor (cleaned protein) for optimal conformation. The grid center (X = 16.082, Y = 4.657, Z = 10.976) and box size (X = 84, Y = 94, Z = 46) were used. And the spacing was set to be 1.00 Å. 2.4 ADMET Prediction The absorption, distribution, metabolism, excretion and toxicology of a substance in and through the human body are dealt with by ADMET characteristics (Balani et al., 2005). The modeled ligands (A–F) were evaluated for their ADME properties using SwissADME software (Daina et al., 2017; Oyebamiji et al., 2022) for accessing their oral-bioavailability and drug-likeness features. These assist in studying the ligands’ pharmacokinetics and pharmacodynamics properties (Iwaloye et al., 2021). Molecular weight, hydrogen bond donor (HBD), hydrogen bond acceptor (HBA), blood–brain barrier (BBB), human intestinal absorption (HIA) are all predicted significant ADME properties. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.4.2022.p27-36 Original Article revista.iq.unesp.br 31 Eclética Química Journal, vol. 47, n. 4, 2022, 27-36 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.4.2022.p27-36 Figure 4. 2D structure of interaction between compound (a–f) and nitroreductase Rdxa protein (PDB ID: 3QDL). 3. Results and Discussion 3.1 Calculated Descriptors The frontier orbital electron densities of atoms in a molecule can be used to analyze the electron donor acceptor interaction (Akintelu et al., 2021). The 2D structures for the studied compounds are as shown on Tab. 1. The frontier molecular orbital energies (EHOMO and ELUMO) are used to determine how a molecule interacts with the other species. The EHOMO orbital energy donates electron, since it is the outermost (highest energy) orbital containing electrons. In contrast, the ELUMO orbital accepts electrons since it is the innermost (lowest energy) orbital that can accept electrons (Raj et al., 2015). According to the frontier molecular orbital theory, the interaction between the HOMO and LUMO of reactants formed the transition state. The EHOMO and ELUMO are directly related to the IP and EA respectively (Eqs. 1 and 2). Higher EHOMO signify that the compound has stronger ability to donate electron(s) to the neighboring compound, the better ability of its drug-likeness properties, as well as the ability of such compound to inhibit receptor (Gao et al., 2010). The band gap (Eg/EHOMO–ELUMO) is also an important parameter that reflects the chemical activity of the molecules. The Eg and associated molecular/ physicochemical properties are as presented in Tab. 2. More so, the HOMO π-electrons are delocalized on the 5-nitroimidazole ring in compounds A, B, D and E, delocalized on the entire molecules in compound F, but localized on thiophenylethyl substituent of compound C. However, the LUMO π-electrons are more localized on the nitro (NO2) group substituent of the nitroimidazole ring in compounds A, B, D, E and F, but are more localized on the 5-nitroimidazole ring in compound C. This attests to studied compounds’ intramolecular charge transfer characteristic properties (Kulhánek et al., 2012). The lowest and highest Eg values were recorded for compound C (3.94 eV) and E (4.63 eV) respectively; a strong indication of highest distribution of charges, and hence, the probability of higher chemical activity of compound C (R = SPh3) compared with the other compounds (Oyebamiji et al., 2021a). 𝐼𝑃 = 𝐸𝐻𝑂𝑀𝑂 (1) 𝐸𝐴 = 𝐸𝐿𝑈𝑀𝑂 (2) The partition coefficient (lipophilicity / log P) plays important roles in drugs design (Méndez-Lucio et al., 2017). It has been described as the main physicochemical determinant that influences the bioavailability, permeability, and penetrability of pharmacophore in biological membranes, and toxicity of the compounds. Their values are therefore used as determinants in some industrial processes, such as agricultural chemistry, drug formulation and flavoring of finished products (Lipinski et al., 2020; Oyebamiji et al., 2021b). According to the Lipinski’s rule of 5 (MW ≤ 500 amu, LogP [octanol- water partition coefficient] ≤ 5, HDB [total number of N–H and O–H bonds] ≤ 5 and HBA [total number of N and O atoms] ≤ 10) (Erazua et al., 2021), problem is likely to be encountered in the oral usage of this drug- like compound if log P value is higher than 5 (Stefaniu and Pintilie, 2018). The log P for all the studied compounds (Tab. 2) were within the acceptable range, which therefore showed that the compounds can be taken https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.4.2022.p27-36 Original Article revista.iq.unesp.br 32 Eclética Química Journal, vol. 47, n. 4, 2022, 27-36 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.4.2022.p27-36 orally. Compounds D, E, F have their log P values (0.59– 0.7) less than 1, being closer to that of the standard— metronidazole (0.42). Furthermore, for compounds to be useful in drug formulation targeted at central nervous system, and intestinal absorption, their log P should fall in the range; 1.35–1.8 (Adegoke et al., 2020). This was observed for compounds B (1.28), while the log P for compound C is slightly greater than 3 (Tab. 2). Table 2. Calculated descriptors for the studied compounds. Mol A B C D E F MW (amu) Molecular weight 171.15 155.15 277.34 199.16 200.15 185.18 DM (Debye) Dipole moment 4.55 4.89 2.98 4.29 3.88 3.59 EHOMO (eV) Highest occupied molecular orbital –6.80 –6.90 –6.26 –7.03 –7.35 –6.95 ELUMO (eV) Lowest unoccupied molecular orbital –2.26 –2.29 –2.32 –2.41 –2.72 –2.39 Band Gap Band gap 4.54 4.61 3.94 4.62 4.63 4.56 HBA Hydrogen bond accept 5 4 5 5 5 5 HBD Hydrogen bond donor 1 0 0 1 0 0 Log p Lipophilicity 0.42 1.28 3.45 0.70 0.59 0.78 Ovality Ovality 1.30 1.29 1.47 1.35 1.35 1.36 PSA (A2) Polar surface area 65.15 46.30 46.06 80.15 85.44 53.77 SE (KJ/mol) Solvation energy –37.24 –27.70 –45.09 –43.64 –34.32 –31.80 Note: Referenced drug = Compound A = metronidazole. Solvation energy, a measure of interaction of solute with solvent that leads to stabilization of species in solution, is also highly significant in drugs development. The highest solvation energies recorded for compound C is an indication that its interaction with solvent will be more thermodynamically favored than other studied molecules (Choi et al., 2013). The trends in the polar surface area of the compounds (C < B < F< A < D < E) differ from their volumes (B < A< E < F < D < C), and molecular weight (B < A< F < D < E < C) variations. Ovality is related to molecular surface area and van der Waal’s volume; it increases with increasing structural linearity and deviate from spherical form, which is usually 1 for spherical shape molecules (Abdul-Hammed et al., 2020). The reported trend in the ovality values of the studied compounds: B (1.29) < A (1.30) < D (1.35) =E (1.35) < F (1.36) < C (1.49), suggests that compound C vary more greatly from spherical shape than the other compounds. The dipole moment and polarizability of molecule which measure the bond properties (induction polarization), charge densities and nonbonding interactions between ligand and receptor of molecules follow the trend: B > A > D > E > F > C. As reported by Adeoye et al. (2017) and Oyewole et al. (2020), the unpredictable properties of drug-like molecules may arise as a result of large dipole moment value, molecules with better charge distribution and increasing distance will have higher dipole moment and polarizability. Thus, the studied compounds may possibly have strong nonbonded connections with the target nitroreductase Rdxa proteins (PDB ID: 3qdl). 3.2 Molecular Docking and ADME Studies A docking study was used to predict the preferred orientation or correct conformation of the ligand in the active site of the protein. The binding energy measure of binding affinity is an important parameter generated from molecular docking to provide information on the strength of the interaction between the ligand and receptor. The interaction is spontaneous; the greater the binding affinity (in term of negativity), the better the inhibition (Adeoye et al., 2022; Ibrahim et al., 2019). Consequently, the five studied compounds (B–F) were docked against the target (PDB ID: 3qdl) to determine the nonbonding interactions present in the studied complex using metronidazole (A) as the standard. The calculated binding affinities for the compounds A–F were –18.8, –18.0, –17.2, –21.3, –21.3 and –18.4 kJ mol–1, respectively. Compounds D and E have the same binding affinity (–21.3 kJ mol–1) and inhibition constant (7.8) which were compared with the referenced drug (compound A [metronidazole]) (Tab. 3 and Fig. 4). It was observed that the addition of –COOH and –NO2 to the parent compound enhanced it inhibit activity. Also, as shown in Tab. 2, lower ability of compounds D and E to donate electron to target compounds as well as their greater capacity to receive from the nearby compounds enhanced it capability to inhibit nitroreductase Rdxa proteins than others studied compound as well as the referenced drug (compound A). https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.4.2022.p27-36 Original Article revista.iq.unesp.br 33 Eclética Química Journal, vol. 47, n. 4, 2022, 27-36 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.4.2022.p27-36 Table 3. Calculated scoring, residues, inhibition constant and types of non-bonding interactions between 2HMN derivatives and Nitroreductase Rdxa Protein (PDB ID: 3qdl). Compounds Binding Affinity (kJ mol–1) Residue involved in the interaction Inhibition constant K1 (nmol L–1) Types of nonbonding interaction involved A –18.8 SER 199, SER 196, LYS 198, SER 18, ARG 200 6.1 Conventional hydrogen bond π-carbon, π-donor hydrogen bond B –18.0 ARG 16, LYS 198, ARG 200, SER 18 5.6 π- π stacked, π-alkyl C C –17.2 PHE 3, LEU 153 5.2 Conventional hydrogen bond, π-donor hydrogen bond D –21.3 ARG 16, GLN 17, SER 199, SER 196, LYS 198, SER 18, ARG 200 7.8 Conventional hydrogen bond, π-carbon π-donor hydrogen bond E –21.3 SER 199, SER 196, LYS 198, ARG 16, SER 18, ARG 200 7.8 Conventional hydrogen bond, π-carbon π-donor hydrogen bond F –18.4 HIS 17, SER 199, SER 196, LYS 198, SER 18, ARG 200 5.9 Conventional hydrogen bond, π-alkyl, π-cation carbon- hydrogen bond Note: Referenced drug = Compound A = metronidazole. These compounds proved to possess highest tendency to inhibit nitroreductase Rdxa proteins (PDB ID: 3qdl) and may likely be more potent than other studied ligands. The amino acid residues involved in the interactions and the types of nonbonding interactions involved are as displayed in Fig. 4 and Tab. 3. Furthermore, compounds D and E’s ADME features with the best efficient calculated binding affinity were comparable with the standard metronidazole (Tab. 4). Table 4. Drug-likeness prediction. Compounds Molecular weight Log P HBD HBA Violations A 171.156 0.42 1 5 0 B 155.157 1.28 0 4 0 C 277.348 3.45 0 5 0 D 199.166 0.70 1 5 0 E 200.154 0.59 0 5 0 F 185.183 0.78 0 5 0 The higher the HIA, the better the compound’s tendency to be absorbed upon oral administration (Oyebamiji et al., 2020). As observed in Tab. 5, the values of HIA for the studied compounds are positive and correlated with the standard. This further proved that the selected compounds have capacities to be absorbed in the intestine. The ability to cross the BBB for compounds D and E are also closer to the existing standard drug (metronidazole), while the molar solubility in aqueous state (log S) values of the selected compounds and standards fall within the recommended range of 1 to 5 (Ibrahim et al., 2018). The observed ADME factors indicate that the selected compounds and the standards have better absorption and distribution properties. The Caco-2 permeability reveals the permeability on lipid absorption and metabolism of the studied compounds (Semire et al., 2017). The probability of this was higher in compound D, but little lower than the standard in the ligand E. Also, in terms of metabolic activities of the selected ligands, compounds D and E are non-inhibitors and nonsubstrates for microsomal enzymes (CYP450 2C9, CYP450 2D6 and CYP450 2C19), similar to the standard. A noninhibitor of CYP450 means that the molecule will not hamper the biotransformation of the drugs metabolized by CYP450 enzyme (Nisha et al., 2016). https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.4.2022.p27-36 Original Article revista.iq.unesp.br 34 Eclética Química Journal, vol. 47, n. 4, 2022, 27-36 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.4.2022.p27-36 Table 5. Predicted ADME properties of the studied compounds. Compound D Compound E Compound A (Metronidazole) Mode Result Probability Result Probability Result Probability Blood-Brain Barrier BBB+ 0.114253 BBB+ 0.12801 BBB+ 0.173454 Human Intestinal Absorption HIA+ High HIA+ High HIA+ High Caco-2 Permeability Caco-2 High Caco2+ High Caco2+ High Log S ESOL –0.67 ESOL –0.86 ESOL –1.00 Solubility (mg/ml) Very soluble 4.32+01 Very soluble 2.76+01 Very soluble 1.72+01 Log S Ali –1.00 Ali –1.49 Ali –1.29 P-gp substrate Substrate No Substrate No Substrate No Log p ILOGP 0.77 ILOGP 0.59 ILOGP 1.16 Lipinski’s rule Yes Yes Yes CYP450 2D6 Substrate Noninhibitor No Substrate No Noninhibitor No CYP450 2C9 Inhibitor Noninhibitor No Noninhibitor No Noninhibitor No CYP450 2D6 Inhibitor Noninhibitor No Noninhibitor No Noninhibitor No CYP450 2C19 Inhibitor Noninhibitor No Noninhibitor No Noninhibitor No CYP450 3A4 Inhibitor Inhibitor No Inhibitor No Inhibitor No CYP450 3A4 Substrate Substrate No Substrate Substrate Substrate Substrate Synthetic accessibility 2.23 2.53 2.30 Ghose 0 0 0 Vegar 0 0 0 Pain 0, Alert 0.12801 0, Alert 4. Conclusions This study was carried out to determine the effects of substituents: –OH, H, –SPh, –COOH, –NO2 and –OCH3 on the chemical activities and interactions of six nitroimidazole derivatives on the target nitroreductase Rdxa protein (PDB ID: 3qdl) for the treatment of H. pylori infection. The nonbonding interactions and the calculated binding affinities that exist between the six compounds and the nitroreductase Rdxa protein were identified. The ADME features showed that substituted –COOH and –NO2 nitroimidazole derivatives has the same binding energies (kJ mol–1) and higher tendency to inhibit target nitroreductase Rdxa protein (PDB ID: 3qdl) than the referenced drug despite their higher band gaps. The compounds are also noninhibitors and non- substrates for microsomal enzymes (CYP450 2C9, CYP450 2D6 and CYP450 2C19), with capacities to be absorbed in the intestine and ability to cross the BBB comparable with the standard. Authors’ contribution Conceptualization: Adeoye, M. D.; Oyebamiji, A. K. Data curation: Adeoye, M. D.; Oyebamiji, A. K. Formal Analysis: Adeoye, M. D.; Oyebamiji, A. K. Funding acquisition: Ashiru, M. J.; Adigun, R. A. Investigation: Adeoye, M. D. Methodology: Adeoye, M. D. Project administration: Adeoye, M. D. Resources: Olalere, O. H. Software: Semire, B. Supervision: Semire, B. Validation: Oyebamiji, A. K. Visualization: Adeoye, M. D.; Oyebamiji, A. K. Writing – original draft: Adeoye, M. D. Writing – review & editing: Oyebamiji, A. K. Data availability statement All data sets were generated or analyzed in the current study. Funding Not applicable Acknowledgments We are grateful to Computational Chemistry Research Laboratory, Chemical Sciences Department, Fountain University and Mrs. E. T. Oyebamiji as well as Miss Priscilla F. Oyebamiji for the assistance in the course of this study. References Abdul-Hammed, M.; Semire, B.; Adegboyega, S. A.; Oyebamiji, A. K.; Olowolafe, T. A. 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