Biology, Medicine, & Natural Product Chemistry ISSN 2089-6514 (paper) 

Volume 14, Number 2, October 2025 | Pages: 843-856 | DOI: 10.14421/biomedich.2025.142.843-856 ISSN 2540-9328 (online) 
 

 

 

 

DFT Study and ADMET Investigation of Bioactive 2-Phenoxyquinolines 

 
Oluwafemi S. Aina1,2*, Mujeeb O. Rofiu1, Luqman A. Adams1, Oluwole B. Familoni1 

1Department of Chemistry, University of Lagos, Lagos, Nigeria. 
2Department of Biological Sciences, Trinity University, Lagos, Nigeria. 

 

 

Corresponding author* 
oluwafemiaina100@gmail.com 

 

 
Manuscript received: 26 August, 2025. Revision accepted: 14 October, 2025. Published: 20 October, 2025. 

 

 

Abstract 

 

Pharmacologically active quinoline compounds show interesting functionalities. However, there is still a dearth of information on the 

potential wide applications of the quinoline scaffolds especially when the substituents on the rings or functionalities are modified. In this 

study 2-phenoxyquinoline-3-carbaldehyde derivatives were synthesized and investigated using DFT to determine the molecular 

parameters, electronic and chemical reactivity descriptors including their possible application as drug candidates. Geometry optimisations 

were carried out using Becke three-parameter hybrid functional combined with Lee-Yang-Parr correlation functionals and augmented basis 

set with added sets of diffuse s- and p-functions: BL3YP /6-311++G(d,p). Drug-likeness scores and bioactivity prediction were carried out 

using the webserver programs ADMET Sar 2. Our results showed slightly lower energy values in water than in ethanol depicting high 

reactiveness of the 2-phenoxyquinolines in water especially compounds with fluoro- and methoxy substituted having the lowest Egap of 

3.79 eV and 3.381 eV respectively. The methoxy substitution confers higher susceptibility to electron transfer and chemical reactive in 

aqeous medium. The ionization potential energies were lower in water and ethanol when compared to the other gas states calculated 

values. The MEP surfaces of all the compounds investigated reveals the ether oxygen atoms and carbonyl groups as necessities for 

effective antioxidant properties. It is noteworthy that five of the compounds investigated have high activity values above 3.0 octanol–

water partition coefficient value indicating an excellent inhibitory activity and strong chemical reactivity. Good oral bioavailability was 

shown by the compounds depicting their excellent activity as kinase inhibitors, nuclear receptor compounds and enzyme inhibitors. It is 

noteworthy that cytochromes CYP2C19, CYP2C29, CYP2D6 and CYP3A4 are not inhibited and therefore do not pose potential adverse 

drug reactions or toxicity. Interestingly, only one compound showed one violation. Consequently, such scaffolds are potential drug 

candidates. 

 

Keywords: 2-phenoxyquinolines; drug-likeness; cytochrome substrate; structural activity relationship. 

 

 

INTRODUCTION 
 

Quinoline an aromatic organic compound is prevalent in 

various pharmacologically active synthetic and natural 

compounds. It is characterized by a double-ring structure 

containing a benzene ring fused to pyridine at two 

adjacent carbon atoms (Jain et al., 2016) and have been 

found highly useful as antimalarial, anticancer, anti-

inflammatory agents, etc. (Dib et al., 2021) leading to its 

attraction of great interest in the scientific community. 

Researchers have synthesized hybrid quinoline scaffolds 

using different procedures (Figure 1a). 

Conventional chemotherapy kills most tumour cells 

and it is believed that cells left behind might recur 

thereby becoming stem cells which are likely to share 

similar properties of parent cells, such as resistance to 

drugs and toxicity via ATP-binding cassette (ABC) 

transporter expressions (Suzuki et al., 1997). A series of 

quinoline derivatives has been reported to show MDR-

reversing activities in K562 cancer cells that are resistant 

to doxorubicin (an anthracycline multi-cancer therapy) 

which has been identified as a novel, orally active, 

quinoline-derivative inhibitor of ABCB1 ⁄ P-gp 

(Kouznetsov et al., 2016). Drugs and candidates such as 

Lenvatinib, Cabozantinib and Dofequidar are anticancer 

drugs based on the C-4 and C-5 substituted 

aryloxyquinoline and alkoxyquinoline derivatives 

respectively have also been found to contain high 

efficacies as shown in Figure 1b (Suzuki et al., 1997; 

Katayama et al., 2009). 

 

https://doi.org/10.14421/biomedich.2025.142.843-856


 

 
 

844 Biology, Medicine, & Natural Product Chemistry 14 (2), 2025: 843-856 

 

 

 
Figure 1a. Some applications of 2-phenoxyquinoline derivatives. 

 

 

 
Figure 1b. Anticancer drugs with the alkyl/aryloxyquinoline moiety. 

 
 

METHODOLOGY  
 

Different novel methods have resulted to synthesis of this 

bioactive moiety for more than five decades and these 

methodologies have all been modified with eco-friendly 

transition metal mediated, traditional methods, 

microwave or ultrasonic irradiation, oxidation of the 

corresponding alcohols or greener protocols (Sharma et 

al., 2018; Ramírez et al., 2022). Amongst the 

contemporary methodologies are the conventional 

methods such as condensation of amines and carbonyl 

compounds with numerous substrate scope (Kouznetsov 

et al., 2005; Iwai & Sawamura, 2015). 

 

Synthesis of precursors and target compounds  

Vilsmeier-Haack reaction of acetanilides, one of the 

practically important routes to synthesis of 2-

chloroquinoline-3-carbaldehydes, involves the processes 

of chlorination, formylation and cyclization of 

acetanilides by the action of the Vilsmeier ́s reagent 

(DMF/POCl3) to afford 2-chloroquinoline-3-

carbaldehydes as shown in scheme 1 (Meth-Cohn et al., 

1981).  The adducts obtained from Vismeier reaction 

could undergo substitution reaction at positions 2 and 3 

where the active chloro and the aldehyde groups could 

lead to numerous functionalization under appropriate 

reagents (Abdel-Wahab & Khidre, 2013). 

 

 

 
Scheme 1. Synthesis of 2-chloroquinoline-3-carbaldehyde and its phenoxylated adducts as precursors (cf: Bakthadoss & Aina et al, 2024). 

 



 

 
 

 Aina et al. – DFT Study and ADMET Investigation of Bioactive 2-Phenoxyquinolines 845 
 

 

 
Scheme 2. Synthesis of acetoxylated and benzoylated 2-phenoxychloroquinoline-3-carbaldehydes via nitrogen-directed palladium-catalysed sp2 C-H 

activation strategy (cf: Bakthadoss & Aina et al, 2024). 

 

 

Interest in the use of these bioactive organic 

molecules possessing high degree of delocalization has 

increased in the recent time due to presence of weak van 

der Waal’s and hydrogen bonds resulting to better 

enzyme-compound interactions (Kumar et al., 2017). To 

this end, our study therefore presents density function 

theory (DFT) with detailed chemical reactivities of eight 

(8) 2-phenoxyquinoline derivatives shown in Figure 2 

synthesized using the methods presented in Scheme 2 to 

investigate their possible application as drug candidates 

with emphasis on their toxicity. Quantum mechanical 

calculations were also performed to examine their 

molecular structures, parameters, molecular electronic 

and chemical reactivity descriptors.  

 

Computational Methodology 

The coordinates of the structures of synthesised 

compounds were generated from Avogadro 14.0 while 

molecular optimization calculations were done using the 

Orca 4.2.1 Quantum Chemical Software. (Neese, 2017). 

The geometry optimisation was carried out using the Becke 

three-parameter hybrid functional combined with Lee-

Yang-Parr correlation functionals and augmented basis 

set with added sets of diffuse s- and p-functions: BL3YP 

/6-311++G(d,p) (Ennaba, 2017; Kodikara et al., 2018; Al 

Hasanat, 2017). The choice of selected functional and the 

basis set were based on its reliability in published reports 

(Haroon et al., 2019). A single-point gas- phase, water-

phase and ethanol-phase optimizations were carried out 

using time-dependent density functional theory (TD-

DFT) 13 keyword and solving for 50 excited states. All 

calculations in solvent was performed using the CPCM 

keyword together with the SMD solvent model (Fleming 

et al., 2011; Ho & Ertem, 2016). Drug-likeness scores and 

bioactivity prediction were carried out using the webserver 

programs such as ADMET Sar 2 (available at 

http://lmmd.ecust.edu.cn/admetsar2) and molinspiration -

-cheminformatics (available at 

https://www.molinspiration.com/cgi-bin/properties) 

(Voiculescu et al., 2022). 

 

 

RESULT AND DISCUSSION 
 

Chemical reactivity descriptors 

DFT tools used in this study give a concise structure-

chemical reactivity report of 2-phenoxyquinoline-3-

carbaldehyde derivatives (Figure 2) to provide an 

understanding of the chemical reactivity properties 

whose descriptors are presented in Table 1. Frontier 

molecular orbitals (FMOs) energies were used to 

calculate these chemical reactivity descriptors obtained 

from conceptual DFT. The energy gap, Egap is defined as 

the energy difference between EL (the lowest unoccupied 

molecular orbital, LUMO) and EH (energy of the highest 

occupied molecular orbital, HOMO) which determines 

the chemical reactivity and kinetic stability of the organic 

molecule. The lower the energy gap, the more reactive a 

molecule is, indicating the compound is more susceptible 

to reacting with proteins or enzymes (Miar et al., 2021). 

The results of the energy gaps (Table 1 and Figure 3) 

showed slightly lower energy values in water than in 

ethanol. Since, the preferred medium of drug delivery is 

water, this depicts the highest reactiveness of the 2-



 

 
 

846 Biology, Medicine, & Natural Product Chemistry 14 (2), 2025: 843-856 

 

 

phenoxyquinolines in water, with 7 and 3 having the 

lowest Egap of 3.381 eV and 3.79 eV respectively. The 

concentration of the molecules is proportionately the 

inverse of the energy gap. That is, the lower the energy gap 

the higher the concentration of the molecule in water solution 

and therefore it shows a greater activity of the 2-

phenoxyquinolines in aqueous medium. The difference in 

the energy gap may be mostly attributed to the 

differences in their functional groups (Table S1). This 

difference can be attributed to the acetoxyl and benzoyl 

substituents at para position of the phenoxy group. In 

compounds 3, 7 and 8, the main chromone skeleton 

(quinoline) has both electron withdrawing and electron 

donating substituents attached to it. These substituents 

may increase or decrease the electron density in the 

quinoline ring thereby activating or deactivating the 

ring. The lower energy gap for 3 and 8 may be attributed 

to F which shows a negative inductive effect due to its 

high electronegativity and withdraws the electron density 

from the quinoline ring, so it deactivating the group. The 

more electrophilic benzyl group in the chromone 

backbone allows electronic interactions that are pivotal to 

the quinoline reactivity. Also, the methoXyl groups on 

the chromone structure of compound 7 which has the 

lowest energy gap (3.381 eV) activate the benzene ring 

towards electrophilic substitution and this is also 

favourable for the radical scavenging activity of the 

quinoline ring. The feasibility of a molecular system to 

exchange electron density or an electron escaping from 

such system to the surrounding environment at the 

ground state can be expressed as the energy changes of 

the molecular system with respect to the number of 

electrons at a fixed external potential, µ (Domingo et al., 

2016). 

 

 

 
Figure 2. Structures of synthesized phenoxyquinoline compounds investigated. 
 

 

The calculated electronic chemical potential of the 

molecules shows no significant difference for the 2-

phenoxyuinolines. In water, the chemical potential values 

range from -4.688 eV (8) to -4.301 eV (7) while in 

ethanol, it ranges from -4.681eV (8) to -4.294 eV (7) 

with both media having the ascending and descending 

order of 7, 3, 5, 8, 1, 2, 6 and 4 hardness and softness, η 

and s respectively define the extent of resistance and 

susceptibility to polarization or transfer of electron cloud 

of atoms, ions or molecules in response to a chemical 

process (Islam & Ghosh, 2011). These periodic 

properties calculated as global softness, s are the inverse 

of global hardness, η. Compound 7 shows the most 

minor resistance or highest susceptibility to charge or 

electron transfer with η and s values (1.691 eV and 0.592 

eV) in water respectively. Conversely, compound 4 has η 

value of 2.106 eV and s value of 0.475 eV in aqueous 

medium. Therefore, of all the 2-phenoxyuinolines 

compounds, 7 is the most susceptible to electron transfer 

and the most chemically reactive in aqeous medium 

while compound 4 poses the highest resistance to the 

transfer of electron density in the medium and hence, the 

least reactive. Electronegativity, χ, represents electron 

attraction power of an atom in a molecule towards itself 

or a measure of molecular electron distribution.23 The 

highly probable electron acceptability of these molecules 

was indicated by high electronegativity values. 

Compounds 8 and 6 had the highest χ value (4.688 eV 

and 4.681 eV) in aqueous medium while 7 had the lowest 

(4.301 eV). A possible explanation for high 

electronegativity for compound 8 and 6 is the presence of 

fluoro group (a deactivating group) with high inductive 

effect. Compound 7, on the other hand has an activating 

group that is mostly resonance donors (+M), that is, 



 

 
 

 Aina et al. – DFT Study and ADMET Investigation of Bioactive 2-Phenoxyquinolines 847 
 

 

methoxyl group. Although it also inductively withdraws 

(–I) electrons, which is a deactivating effect, the 

resonance (or mesomeric) effect is stronger, hence an 

even electron distribution which accounts for the reduced 

electronegativity.  

The information about the physico-chemical 

properties and chemical reactivity phenomena of a 

molecule can also be revealed by a measure of the 

stabilization energy of the molecule when it accepts an 

arbitrary number of electrons approaching from the 

surroundings. This concept is termed electrophilicity 

index (ω) (Tandon et al., 2020). This approach can be 

explained in two ways; the global electro-accepting 

power ω+ and electro-donating power ω−. The 

electrondonating power is a measure of the 

nucleophilicity of the system and it involves the 

destabilizing change in energy required by a system to 

attain zero chemical potential with accompanied a 

decrease in the number of electrons of the system. On the 

other hand, the electronaccepting power ω+ of a 

molecular system, can be defined base on the stabilizing 

energy change of such system when it is saturated with 

maximum number of electrons (Gazquez et al., 2014). 

The net electrophilicty Δω±, describes of 

intermolecular reactivity (Frau & Glossman-Mitnik, 

2017). The results from the calculations show that the 2-

phenoxyuinolines have an average approximate electron 

donating power, ω− of 9 eV. This approximate 

destabilizing energy is higher than the average 

approximate electron accepting power, ω+ of about 6 eV 

except for compound 4 which shows a very lower 

electrophilic index or stabilizing energy change 

accompanying electron gain with ω+ value of 

approximately 1 eV. This suggests that the 2-

phenoxyuinolines are strongly nucleophilic and 

electrophilic but more nucleophilic in reactivity than 

being electrophilic.  

The ionization potential, I and electron affinity values 

also show the relative tendencies of an atoms or molecule 

to gain or lose electrons in reaction and useful in the 

calculation of heats of various reactions and physical 

changes (Smalo et al., 2010). Reactivity is inversely 

proportional to Ionization potential so lower ionization 

potential would depicts a higher the chemical reactivity. 

 

 

Table 1. Chemical reactivity descriptors for the synthesised 2-Phenoxyquinolines. 

 

Cpd Medium EL (eV) EH (eV) Egap (eV) Η S µ ꭓ Ω ω¯ ω⁺ ∆ω± µD I 

1 Gas -2.597 -6.713 4.116 2.058 0.486 -4.655 4.655 1.316 9.345 6.389 15.734 2.597 6.713 

 Water -2.591 -6.625 4.034 2.017 0.496 -4.608 4.608 1.316 9.257 6.424 15.680 2.591 6.625 

 Ethanol -2.565 -6.614 4.049 2.025 0.494 -4.590 4.590 1.301 9.215 6.321 15.536 2.565 6.614 

2 Gas -2.584 -6.769 4.185 2.093 0.478 -4.677 4.677 1.306 9.382 6.298 15.680 2.584 6.769 

 Water -2.599 -6.659 4.060 2.030 0.493 -4.629 4.629 1.319 9.298 6.434 15.732 2.599 6.659 

 Ethanol -2.573 -6.651 4.078 2.039 0.490 -4.612 4.612 1.304 9.259 6.330 15.589 2.573 6.651 

3 Gas -2.750 -6.678 3.928 1.964 0.509 -4.714 4.714 1.414 9.507 7.092 16.598 2.750 6.678 

 Water -2.670 -6.577 3.907 1.954 0.512 -4.624 4.624 1.368 9.313 6.808 16.120 2.670 6.577 

 Ethanol -2.649 -6.554 3.905 1.953 0.512 -4.602 4.602 1.356 9.265 6.731 15.996 2.649 6.554 

4 Gas -2.536 -6.076 3.54 1.77 0.565 -4.306 4.306 1.309 8.695 6.612 15.306 2.536 6.076 

 Water -2.416 -6.628 4.212 2.106 0.475 -4.522 4.522 1.214 9.055 5.714 14.770 2.416 6.628 

 Ethanol -2.388 -6.599 4.211 2.1055 0.475 -4.494 4.494 1.199 8.996 5.623 14.619 2.388 6.599 

5 Gas -2.373 -6.499 4.126 2.063 0.485 -4.436 4.436 1.192 8.884 5.618 14.502 2.373 6.499 

 Water -2.564 -6.514 3.950 1.975 0.506 -4.539 4.539 1.304 9.122 6.386 15.508 2.564 6.514 

 Ethanol -2.528 -6.496 3.968 1.984 0.504 -4.512 4.512 1.283 9.061 6.245 15.306 2.528 6.496 

6 Gas -2.633 -6.801 4.168 2.084 0.480 -4.717 4.717 1.335 9.470 6.481 15.951 2.633 6.801 

 Water -2.642 -6.72 4.078 2.039 0.490 -4.681 4.681 1.343291 9.406582 6.575077 15.98166 2.642 6.72 

 Ethanol -2.615 -6.712 4.097 2.049 0.488 -4.664 4.664 1.327 9.366 6.465 15.831 2.615 6.712 

7 Gas -2.694 -6.140 3.446 1.723 0.580 -4.417 4.417 1.415 8.971 7.337 16.308 2.694 6.140 

 Water -2.610 -5.991 3.381 1.691 0.592 -4.301 4.301 1.368 8.726 7.062 15.788 2.610 5.991 

 Ethanol -2.599 -5.988 3.389 1.695 0.590 -4.294 4.294 1.360 8.708 7.009 15.717 2.599 5.988 

8 Gas -2.771 -6.810 4.039 2.020 0.495 -4.791 4.791 1.420 9.651 7.078 16.729 2.771 6.810 

 Water -2.696 -6.680 3.984 1.992 0.502 -4.688 4.688 1.379 9.438 6.843 16.281 2.696 6.680 

 Ethanol -2.676 -6.686 4.010 2.005 0.499 -4.681 4.681 1.366 9.418 6.749 16.167 2.676 6.686 
 

a Units for the chemical reactivity descriptors are in electron volts (eV) EL: LUMO energy, EH: HOMO energy, Egap: HOMO-LUMO 

energy gap, η: Chemical hardness, S: Chemical softness, μ: Chemical potential, χ: Electronegativity, ω: Electrophilicity index, ω-: 

Electron donating power, ω+: Electron accepting power, Δω±: Net electrophilicity, μD: Dipole moment, I: Ionization potential, g: gas 

phase, w: water and eth: ethanol. 

 

 

In water and ethanol, the ionization potential energies 

were lower when compared to the other gas states 

calculated values. This emphasizes the fact that the 

chemical reactivity of the 2-phenoxyquinolines is well 

improved in water and ethanol media. Since, the desired 

medium (water) gives favourable intermolecular 

interactions via hydrogen bonding, therefore, it reflects in 

lower ionization potential. Compound 7 has the lowest I 

value (5.991 eV) in water compared to other 2-

phenoxyquinolines.  

 

 



 

 
 

848 Biology, Medicine, & Natural Product Chemistry 14 (2), 2025: 843-856 

 

 

 
 

Figure 3. Comparison of the energy gaps in gas-phase, water and ethanol. 

 

 

Atomic charge and electrostatic potential 

 Molecular electrical charge is the driving force of 

electrostatic interactions characterized by electron 

density playing an important role in chemical reactions 

and physicochemical properties (Wang & Truhlar, 2014). 

Descriptors that are charge based are often employed as 

chemical reactivity indices or as a measure of weak 

intermolecular interactions. The partial charge or electron 

density distribution in a molecule is factor to 

determination of its reactivity description. The Mulliken 

atomic charges MAC, may be linked to other chemical 

parameters such as dipole moment, electric potentials, 

chemical shifts, electronic structure, molecular 

polarizability and others (Sumrra et al., 2021). A uniform 

distribution of charge was found for all molecules. For 3, 

5, and 7, which had the lowest energy gap in aqeous 

medium and were the most reactive, they had the highest 

negatively charged atom (-2.518 a.u, −2.609 a.u. and -

2.021 a.u.) which is the carbon atom of the imine group 

at C9 and C14 positions attached to pyridine nitrogen, 

respectively (Figure 2). This charge is significant for the 

bioactivity of the molecules due to the role the F, –OCH3 

groups play in scavenging radicals.  

 

Molecular electrostatic potential surface 

Molecular electrostatic potential (MEP) surfaces enhance 

determination of the reactivity of chemical compounds 

and it is related to electron density and is a useful 

chemical descriptor that gives information about sites of 

nucleophilic attacks, electrophilic attacks and hydrogen 

bonding interactions (Demircioglu et al., 2019). The blue 

region indicates the positive potential of the molecule as 

the area where there is proton repulsion (that is 

electrophilic attack) while the red region has negative 

potential and represents proton attraction (nucleophilic 

attack) (Sheikhi et al., 2016). 

 

 
 Compound 3 Compound 5 Compound 7 
 

Figure 4. Representative optimised structures of synthesized 2-Phenoxyquinolines. 

 

 

 
 Compound 3  Compound 5 Compound 7 
 

Figure 5. Representative atomic charge distribution in synthesized 2-Phenoxyquinolines. 

0

1

2

3

4

5

1 2 3 4 5 6 7 8

Eg
ap

 (
eV

)

Gas

Water

Ethanol



 

 
 

 Aina et al. – DFT Study and ADMET Investigation of Bioactive 2-Phenoxyquinolines 849 
 

 

All the 2-phenoxyquinolines simulated in this study 

have MEP surfaces with an overall region of positive 

potential around protons of the C8, C10, and C6 while 

areas of negative potential are around delocalized pi-

electrons, the ether oxygen atoms and that of the 

carbonyl groups which verifies the necessity of the ether 

and carbonyl groups for effective antioxidant properties 

of the quinolines. The carbonyl of the aldehyde and 

acetate groups of the 2-phenoxyquinolines contributes 

effectively to the reactive oxygen and hydrogen species’ 

scavenging abilities of the compounds as they offer 

stability.  It is a known phenomenon that the regions of 

negative potential in the 2-phenoxyquinolines 

compounds will have an affinity for the positively 

charged side groups of amino acids (arginine, histidine 

and lysine) and regions of positive potential of the will 

bind to the negatively charged side groups of amino acids 

such as glutamic acid and aspartic acid (Shinde, 2021). 

 

UV–vis spectroscopy 

UV–visible spectroscopy has emerged as the most 

favoured technique to evaluate conjugated organic 

compounds such as quinoline and its derivatives as the 

ring in these bioactive molecules have the ability to 

absorb UV light. Few coloured derivatives also absorb in 

the visible region thus enabling UV–visible spectroscopy 

one of the appropriate techniques their bioactivity 

(Ramešová et al., 2012). Total antioxidant activity is 

measured by taking absorbance against water to calculate 

the percentage of inhibition. The presence of the 

carbonyl groups of the 2-phenoxyquinolines also 

contributes to an increase in the absorbance. Absorption 

peak is associated with an electron transition from the 

ground state to its excited state with corresponding 

excitation energy and single-point (SP) energy 

calculation provides the HOMO and LUMO energies as 

shown in Table 1.  

It has been reported that ethanol and water or a 

mixture of these solvents are suitable since the oxygen of 

the carbonyl groups easily bond with the hydrogen of the 

water molecules hence their solubility in the solvents are 

expected (Blume et al., 1988). We chose water as the 

solvent for the UV–vis calculation since this is preferred 

medium for drug delivery. The maximum absorption 

wavelength (λmax) of the 2-phenoxyquinolines in water 

and the excitation energies show that maximum 

wavelength of absorption is inversely proportional to the 

excitation energy as shown in Table 2, Figure 8. 
 

 

 

Table 2. UV–visible Spectroscopy. 

 

Compound Orbitals Extinction coeff Oscil strength 1st Excitation E (eV) Absorption  

1 79 -80 0.548 0.741 3.3711 367.8 

2 87 - 88 0.729 0.854 3.159 392.5 

3 91 - 92 0.89 0.943 2.865 432.8 

4 83 - 84 0.223 0.472 3.368 368.2 

5 95 - 96 0.791 0.889 3.186 389.2 

6 94-95 0.059 0.243 3.375 367.4 

7 106-107 0.94 0.969 2.785 445.2 

8 102 - 103 0.317 0.563 3.287 377.2 

 

 

 
 Compound 3 Compound 5 Compound 7 
 

Figure 6. Representative HOMO-LUMO of synthesized 2-Phenoxyquinoline-3-carbaldehydes. 

 



 

 
 

850 Biology, Medicine, & Natural Product Chemistry 14 (2), 2025: 843-856 

 

 

 
 Compound 3 Compound 5 Compound 7 
 

Figure 7. Representative molecular electrostatic potential (MEP) surface of synthesized 2-Phenoxyquinoline-3-carbaldehydes. 
 

 

 
Figure 8. Relationship between excitation energy and maximum absorption wavelength. 

 
 

 

Considering the fact that the promotion of an electron 

from the ground state to the excited state at longer 

wavelengths require low energy, it is hence apparent the 

compound 7 with the lowest excitation energy and the 

highest wavelength, implies most activity while 6 with 

highest excitation energies has lowest activity. From the 

time-dependent density functional theory (TD-DFT) 

calculations, electronic transitions information including 

which transition orbital was involved, oscillator strength, 

extinction coefficient, excitation state energies and the 

electronic states of the transitions support the bioactivity 

of compound 7. 

Molar extinction coefficient, also known as molar 

absorptivity, is an intrinsic property of the molecule 

which is dependent on the atomic, chemical, and 

structural composition. It determines how strongly a 

species absorbs or reflects radiation or light at a 

particular wavelength (Ozdemir & SadoGlu, 2018). 

Compounds 3, 5 and 7 have high molar absorptivity 

(>0.5 eV), hence, they strongly attenuate light while 4 

and 6 have extinction coefficient less than 0.5. Oscillator 

strength is a dimensionless quantity that expresses the 

probability of absorption or emission transitions between 

energy levels of an atom or molecule, that is, a measure 

of excitation probability (Nizar et al., 2021). The high 

oscillator strengths which indicate the high probability of 

excitation gave the strongest transitions (which are 

presented in Table 1) compared to other transitions. 

 

Molecular and physicochemical properties 

Adsorption, distribution, metabolism and excretion 

(ADME) protocols play crucial roles in the development 

of new drug molecules as they outline the dose amounts, 

intervals and overall safety of oral drug administration 

(McGinnity et al., 2007) making the determination of 

physicochemical properties feasible (Nithiyanantham et 

al., 2015) thus providing desirable balance of 

physicochemical properties for safe drug administration 

(Belaidi et al., 2016). The logarithm of octanol–water 

partition coefficient (log POW) is a broadly 

acknowledged measure of lipophilicity and is determined 

for numerous compounds (Poole & Poole, 2003). POW 

is the concentration ratio of the compound distributed 

between n-octanol and water. (Ribeiro et al., 2011; Jalan 

et al., 2010). The partition coefficient is an exceedingly 

important physicochemical parameter in medicinal 

chemistry, beneficial in pharmacology and toxicology, as 

long-established by a large numeral of literature data 

(Balaz, 2009; Sangster, 1997). 

 

 

 

7

2

3

4

5

6

1
8

2,8

3

3,2

3,4

3,6

3,8

4

315 335 355 375 395 415 435

Ex
ci

ta
ti

o
n

 E
n

er
gy

Absorption



 

 
 

 Aina et al. – DFT Study and ADMET Investigation of Bioactive 2-Phenoxyquinolines 851 
 

 
Table 3. Physicochemical parameters for 2-phenoxyquinoline-3-carbaldehydes. 

 

Cp miLog a TPSA b Natoms c MW d nON e nOHNH f Nviolat g Nrotb h Vol i 

1 3.06 65.5 23 307.31 5 0 0 5 267.79 

2 3.46 65.5 24 321.33 5 0 0 5 284.35 

3 2.65 65.5 25 339.32 5 0 0 5 289.28 

4 3.49 65.5 24 321.33 5 0 0 5 284.35 

5 5.59 56.27 28 367.4 4 0 1 5 330.21 

6 2.37 91.81 27 365.34 7 0 0 7 312.31 

7 3.8 101.04 30 409.39 8 0 0 8 354.42 

8 1.94 91.81 29 397.36 7 0 0 7 333.81 

a. Octanol–water partition coefficient as reported in Molinspiration. b. Total polar surface area in Å2. c. Total number of atoms. d. 

Molecular Weight in g mol—1.  e. Number of hydrogen bond acceptors.  f. Number of hydrogen bond donors. g. Number of violations to 

Lipinski’s rule of 5.  h. Number of rotatable bonds.  i. Volume in Å3.  

 

 

Active organic compounds have log P value of 1.6 

upward (Buddensiek et al., 2021) implying a reduced 

inhibitory activity at values below. It is noteworthy to see 

compounds 1, 2, 4, and 7 have high activity values above 

3.0 while compound 5 is well above 5.0 octanol–water 

partition coefficient value indicating an excellent 

inhibitory activity coupled with strong chemical 

reactivity. In the work of Vlahovic et al. (2017), 

hydrophobic substances were reported to have a high 

octanol–water partition coefficient distributed primarily 

in the lipid bilayers of cells while hydrophilic substances 

on the other hand have a low octanol–water partition co-

efficient and are distributed in blood plasma. They also 

showed the linear relationship of the octanol–water 

partition coefficient with log P which explains the high 

miLogP values obtained for compound 5 with a value of 

5.59 as shown in Table 3. This shows the synthesised 2-

phenoxyquinolines to be hydrophobic hence would easily 

distribute in the lipid bilayers. Compound 8 with the least 

value miLogP value of 1.94 is more hydrophilic than 

others and will be more readily distributed in blood 

plasma.  

 

Drug likeness and bioactivity score 

Medicinal chemists use drug-likeness as the essential 

guide via hit-to-lead optimization for drug discovery 

(Sagaama & Issaoui, 2020, Maldonado et al., 2021). 

Pharmacokinetic properties detailed in ADME 

parameters are also strongly affected by physicochemical 

properties (Kumar et al., 2017; Zheng et al., 2013). Since 

drug-like molecules must be soluble in water as well as 

fat, it is therefore necessary that an orally administered 

drug passes through the intestinal lining into the 

bloodstream and is carried to the target immediately after 

ingestion, penetrating the lipid-based cell membrane to 

get into the target cell (Kumar et al., 2017). Increased 

hydrogen bonds leads to increased aqueous solubility 

making the molecule less hydrophobic since it enables 

the molecule to permeate into and through the lipid 

bilayer membrane (Di & Kerns, 2015). As reported by 

Veber and co-workers, drug candidates will have a high 

probability of good oral bioavailability if they meet 

criteria such as: total polar surface area (TPSA) ≤ 140 Å2 

and if the number of rotatable bonds (nrotb) ≤ 10 (Veber 

et al., 2002). Amazingly, all 2-

phenoxyquinolinequinoline-3-carbaldehydes investigated 

in this study fulfil all these criteria. While the 

monoacetoxylated 1-4 and benzoylated 5 2-

phenoxyquinolines have excellent total polar surface area 

(65-74 A2), the di-acetoxylated groups have much higher 

values ranging from 91-101 A2) as shown in Table 3. 

 

 

 

 
Figure 9. Relationship between volume and molecular weight of synthesised 2-Phenoxyquinolines. 

1

2
3

4

5

6

7

8

260

270

280

290

300

310

320

330

340

350

360

307,31 321,33 339,32 321,33 367,4 365,34 409,39 397,36

V
o

lu
m

e

Molecular weight, MW (g/mol)

y = 0.7901x + 27.684 

R2 = 0.9527  



 

 
 

852 Biology, Medicine, & Natural Product Chemistry 14 (2), 2025: 843-856 

 

 

It is noteworthy to express the super permeability of 

compound 5 (with a TPSA value of 56.27 A2) in lipid 

membranes. The Lipinski’s rule of 5 states that for a drug 

molecule to be orally active it should obey important 

rules such as number of hydrogen bond donors (nOHNH) 

≤5, number of hydrogen bond acceptors (nON) ≤ 10, 

molecular weight (MW) ≤ 500, partition coefficient 

(miLogP) ≤ 5 and number of violations (nviolations) ≤ 2 

(Maurya et al., 2020). Interestingly, all the 2-

phenoxyquinoline-3-carbaldehydes comply with the 

Lipinski rule of 5 (Table 3), testifying to their oral 

bioavailabilities as potential drug molecules. In 

compliance, the molecular weight of the compounds is 

directly proportional to the volume of the compounds 

(Table 3, Fig. 9) which confirms their correlation with 

the Pearson correlation co-efficient (r) of 0.97 and R2 

value of 0.94 which states that for an average organic 

molecule, if the bioactivity score is more than 0 then it is 

active, a score ranging from -0.50 to 0.0 indicates 

moderately active and a score of less than -0.50 denotes 

inactivity (Figure 10) (Alodeani et al., 2015; Akintemi et 

al., 2022).   

To further confirm the correlation by the Pearson 

correlation coefficient, the bioavailability of the 

investigated compounds as inhibitors/ substrates were 

carried out using profile depicting bioactivity score as 

presented in Figure 10. It is obvious that compound 5 

exhibit excellent activity as kinase inhibitors, nuclear 

receptor compounds and enzyme inhibitors while 3 

shows good activity as enzyme inhibitor and nuclear 

receptor compound. Compounds 3 and 4 exhibit much 

lower protease inhibitory properties like 2 with moderate 

kinase inhibitory properties. As shown in Figure 10, all 

the compounds exhibit good to moderate activity as 

enzyme inhibitors (EI), G-protein-coupled receptors 

(GPCR), ion channel modulators (ICM), nuclear receptor 

compounds (NRL) and kinase inhibitors (KI). It is 

observed that all the compounds only exhibit moderate 

activity as protease inhibitors (PI). 

 

 

 
 

Figure 10. Profile depicting bioactivity score of compounds 1-8. 

 

 

ADMET/SAR investigation of 2-phenoxyquinoline 

derivatives 

Absorption, distribution, metabolism, excretion 

(ADMET) was analysed based on data generated from 

ADME SAR 2 web server. The values obtained are from 

latest drug-likeness capability tools in drug discovery. 

Most of the parameters correlate positively and are 

presented in Table 5 thus confirming their profile 

depicting bioactivity score in Figure 10. It is noteworthy 

that cytochromes CYP2C19, CYP2C29, CYP2D6, and 

CYP3A4 which are significant enzymes responsible for 

metabolizing commonly used drugs, are not inhibited, 

hence no effect on plasma levels in vivo which can 

potentially lead to adverse drug reactions or toxicity 

while cytochromes CYP2C9 and CYP2D6 act as 

substrates which metabolise pharmacologically inactive 

drugs to active form for easy clearance from the body 

The Ames test is a biological assay to assess the 

mutagenic potential of chemical compounds utilizing 

bacteria to test whether a given chemical can cause 

mutations in the DNA of the test organism. A negative 

test indicates that the chemical is non-mutagenic and 

therefore is not a carcinogen, because cancer is often 

linked to mutation (Czeczot et al., 1990). Suffice to say 

that compounds 7 and 8 gave negative Ames test results 

probably due to the presence of the Fluorine and 

methoxy oxygen atoms at position 6 of the quinoline ring 

which withdraws electrons from the ring via inductive 

effects. Although the methoxy group is electron-donating 

by resonant effect, that does not apply here. Compounds 

1 with fewest substituents shows negative androgen 

receptor binding, situation where a type of nuclear 

receptor activated by binding to any of the androgenic 

hormones, including testosterone and dihydrotestosterone 

in the cytoplasm and is translocated into the nucleus 

-0,4

-0,3

-0,2

-0,1

0

0,1

0,2

0,3

1 2 3 4 5 6 7 8

GPCR ICM KI NRL PI EI



 

 
 

 Aina et al. – DFT Study and ADMET Investigation of Bioactive 2-Phenoxyquinolines 853 
 

 

thereby increasing interfacial stability when compared 

with the other steroid receptors (Shaffer et al., 2004). 

Caco-2 is an immortalized cells line of human colorectal 

adenocarcinoma cell primarily used as a model for the 

measurement of the intestinal epithelial barrier functions 

(Lea, 2015). This returns negative values for compounds 

1 and 6. This could be attributed to the fact that, despite 

being mono- and di-acetoxylated, they are devoid of any 

other substituted elements.  

The only benzoylated compound 5 surprisingly gave 

negative CYP14 substrate value. This cytochrome is an 

HMG-CoA reductase, a factor in the treatment of HIV 

infection by lowering LDL cholesterol and reducing the 

risk of cardiovascular disease such as myocardial 

infarction and stroke. CYP substrates are drugs usually 

metabolized by cytochrome enzymes which require 

metabolism into an inactive form for clearance from the 

body (Galetin et al., 2005). It is obvious that the an extra 

aromatic ring of compound 5 contributed to this effect. 

PPAR gamma is a gene that encodes a member of the 

peroxisome proliferator-activated receptor (PPAR) 

subfamily of nuclear receptors which form heterodimers 

with retinoid X receptors (RXRs) to regulate 

transcription of various genes. Activation of this 

adipocyte predominant transcription factor regulates 

glucose and lipid homeostasis playing significant role in 

the regulation of gene expression of multiple diseases 

including obesity, diabetes and cancer and highlights the 

gene isolation transformation role (Janani & Kumari, 

2015). Compound 2 has extra methyl groups on position 

6 of the 2-phenoxy ring and on the ester group of the 3-

methylacetate of the quinoline ring. These special 

positions of the methyl group could be reason for the 

negative values of the compounds. 

The highest Plasma protein binding value was 

exhibited by only benzoylated compound 5. The 

presence of extra resonance stabilization could have 

contributed to this higher value. Plasma protein binding 

refers to the degree to which medications attach to 

proteins within the blood measuring drug's efficiency as 

it helps determine the degree to which it binds. The less 

bound a drug is, the more efficiently it can traverse or 

diffuse through cell membranes. Plasma proteins, by 

virtue of their high concentration, control the free drug 

concentration in plasma and in compartments in 

equilibrium with plasma, effectively attenuating drug 

potency in vivo (Trainor, 2007). Compound 5 has the 

highest tetrahymena pyriformis value of 1.92. 

Tetrahymena species found in the original T. pyriformis 

group provide an invaluable resource for comparative 

genomic analyses, as evolutionary DNA sequence 

conservation is a valuable predictor of biological 

function under natural selection (Sauvant et al., 1999). 

Thyroid hormone receptors regulate gene expression 

by binding to hormone response elements (HREs) in 

DNA as monomers, heterodimers with other nuclear 

receptors, or homodimers. Dimerizing with different 

nuclear receptors leads to the regulation of different 

genes. They are essential for normal development, 

differentiation and metabolic balance (Zhang & Lazar, 

2000). Compound 5 with the most pi-electrons possessed 

in its four aromatic rings in addition to the two carbonyl 

functions bind with thyroid receptors.  

Drug oral bioavailability is the fractional extent of the 

drug dosage that finally reaches the therapeutic site of 

action. The most relevant measure of lipophilicity with 

regard to oral absorption by passive diffusion is probably 

the distribution coefficient (log D) at pH 6.5, which is the 

pH of the small intestine, where absorption mostly takes 

place (Yoshida & Topliss, 2000) (Yoshida & Topliss, 

2000). Only compound 5 show positive results for human 

oral bioavailability, hence is predicted to reach the site of 

action before being eliminated compared to others.  

Mitochondrial toxicity is a condition in which the 

mitochondria of a body's cells become damaged or 

decline significantly in number; it occurs as a side effect 

of certain antiretroviral drugs used to treat human 

immunodeficiency virus (HIV). Rapid increase in 

reported toxic effects of drugs and pollutants on 

mitochondria have been documented detailing many 

genetic differences leading to mitochondrial diseases 

caused by factors such as as diet, exercise, age, and 

nonchemical stressors (Meyer et al., 2018). Only 

compound 7 shows mitochondrial toxicity from this 

investigation which could be attributed to the presence of 

the methoxy group at position 6. 
 

 

Table 4: Toxicity targets of compounds 1 – 8. 

 

Targets 
Compounds 

1 2 3 4 5 6 7 8 

Hepatotoxicity Inactive Inactive Active Inactive Inactive Inactive Inactive Active 

Carcinogenicity Active Inactive Inactive Inactive Active Inactive Inactive Inactive 

Cytotoxicity Inactive Inactive Inactive Inactive Inactive Inactive Inactive Inactive 

 

 

The respiratory system is a target of toxic effects and 

a major route of absorption of inhaled gases and 

atmospheric particles. Lung toxicosis depends on the 

dose of toxicant delivered to lung tissues and toxicants’ 

acute and chronic effects. Effects can be described in 

terms of tissue damage and lesions and in terms of 

deficits in respiratory system function. Cellular responses 

to toxicants lead to acute effects such as inflammation or 

chronic effects including fibrosis, emphysema, and 

cancer (van der Merwe, 2018). It is noteworthy that all 



 

 
 

854 Biology, Medicine, & Natural Product Chemistry 14 (2), 2025: 843-856 

 

 

the compounds are inactive cytotoxic as shown in Table 

4. While compounds 3 and 8 exhibit slight hepatoxicity, 

compounds 1, 2, 4, 5, 6 and 7 are completely non-

hepatoxic. Compounds 1 and 5 also exhibit minimum 

carcinogenic toxicity while the rest are non-carcinogens. 

To this end, compounds 2, 4, 6, and 7 are potential drug 

candidates as antitumor agents, amidst various other 

pharmacological applications. 

 

 

CONCLUSION  

 

Bioactive quinoline compounds have shown consistent 

applications in drug design. From the DFT study, 

calculated reactivity descriptors, MEP, MAC and optical 

properties support the bioactivity of compounds as 

revealed in their lower energy values in water relative to 

ethanol and gas. ADMET investigation revealed the 

extent of compliance of the compounds as potential 

candidates based on drug-likeness parameters, lead-

likeness, cytochrome inhibition, bioavailability and other 

physicochemical properties. The desired medium (water) 

gives favourable intermolecular interactions via 

hydrogen bonding as reflected in their lower ionization 

potential especially for the 6-methoxy substituted 

functionality with lowest ionization potential value of 

5.991 eV. Generally, uniform distribution of charge was 

found for all compounds especially the 6-fluoro, 

benzoylated and 6-methoxy substituted groups which had 

lower energy gaps in aqeous medium and were the most 

reactive with respective negative values of -2.518 a.u, 

−2.609 a.u. and -2.021 a.u. This charge is significant for 

the bioactivity of the molecules for their role as radical 

scavengers. From MEP and MAC studies, regions of 

negative potentials in the 2-phenoxyquinolines with high 

affinity for the positively charged side groups of amino 

acids provide enablement for good binding interaction. 

Additionally, Pearson correlation co-efficient (r) of 0.97 

and R2 value of 0.94 shows the average bioactivity score 

of all the compounds to be more than 0, therefore are 

active drug candidates. The results presented here can be 

used to further evaluate these bioactive compounds in 

molecular docking studies against infections and 

diseases. 

 

Acknowledgement: We appreciate Prof. O. B. Familoni 

and Prof. L. A. Adams of the Chemistry Department of 

the University of Lagos’s financial support.  

 

Competing Interests: The authors declare that there are 

no competing interests. 

 

 

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