Synthesis, Molecular Modeling, Quantum Mechanical Calculations and ADME Estimation

Studies of Benzimidazole-Oxadiazole Derivatives as Potent Antifungal Agents

Ulviye Acar Çevik 1,2*, Ismail Celik3, Ayşen IŞIK4, Renjith Raveendran Pillai5, Trina Ekawati Tallei6,7,
Rohitash Yadav8, Yusuf Özkay1,2, Zafer Asım Kaplancıklı1
1
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskişehir
26470, Turkey.
2
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Doping and Narcotic Compounds
Analysis Laboratory, Anadolu University, Eskişehir 26470, Turkey.
3
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Erciyes University, Kayseri 38039,
Turkey.
4
Department of Biochemistry, Faculty of Science, Selçuk University, Konya, Turkey.
5
Department of Physics, University College, Thiruvananthapuram, Kerala, India.
6
Department of Biology, Faculty of Mathematics and Natural Sciences, Sam Ratulangi University,
Manado 95115, North Sulawesi, Indonesia
7
The University Centre of Excellence for Biotechnology and Conservation of Wallacea, Institute for
Research and Community Services, Sam Ratulangi University, Manado 95115, North Sulawesi,
Indonesia
8
Department of Pharmacology, All India Institute of Medical Sciences, Rishikesh 249203, India
* Corresponding Author. E-mail: uacar@anadolu.edu.tr; Tel. +90-222-335-0580/3775
Address: Anadolu University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 26470,
Eskişehir, Turkey.
Figure 1. Mass spectrum of compound 4a
Figure 2. Mass spectrum of compound 4b
Figure 3. Mass spectrum of compound 4c
Figure 4. Mass spectrum of compound 4d
Table S1. Predicted ADMET of the studied compounds
ADMET Compounds
Properties 4a 4b 4c 4d Ketoconazol
Water solubility Moderately Poorly soluble Moderately Moderately Moderately
soluble soluble soluble soluble

Pharmacokinetics
GI absorption Low Low Low Low High
BBB permeant No No No No Yes
P-gp substrate Yes Yes Yes Yes No
CYP1A2 inhibitor No No No No No
CYP2C19 Yes Yes Yes Yes Yes
inhibitor
CYP2C9 inhibitor Yes Yes Yes Yes Yes
CYP2D6 inhibitor Yes Yes Yes Yes Yes
CYP3A4 inhibitor Yes Yes Yes Yes Yes

Physicochemical
Properties
Formula C25H20N4O3S C24H17ClN4O2S C24H17FN4O2S C25H20N4O2S C26H28Cl2N4O4
Molecular weight 456.52 g/mol 460.94 g/mol 444.48 g/mol 440.52 g/mol 531.43 g/mol
Num. heavy 33 32 32 32 36
atoms
Num. arom. 26 26 26 26 17
heavy atoms
Num. rotatable 8 7 7 7 8
bonds
Num. H-bond 6 5 6 5 5
acceptors
Num. H-bond 1 1 1 1 0
donors

Druglikeness
Lipinski Yes; 0 Yes; 0 violation Yes; 0 violation Yes; 0 Yes; 1 violation:
violation violation MW>500
Bioavailability 0.55 0.55 0.55 0.55 0.55
Score
Leadlikeness No; 3 No; 2 violations: No; 2 No; 2 No; 3 violations:
violations: MW>350, violations: violations: MW>350,
MW>350, XLOGP3>3.5 MW>350, MW>350, Rotors>7,
Rotors>7, XLOGP3>3.5 XLOGP3>3.5 XLOGP3>3.5
XLOGP3>3.5

Toxicity
Predicted LD50 2604 3048 930 1600 166
(mg/kg)
Predicted Toxicity Class 5 Class 5 Class: 4 Class: 4 Class: 3
Hepatotoxicity Active; Active; Active; Active; Active;
probability probability 0.60 probability 0.62 probability probability 0.76
0.65 0.61
Carcinogenicity Inactive; Inactive; Inactive; Active; Inactive;
probability probability 0.56 probability 0.54 probability probability 0.51
0.54 0.53
Immunotoxicity Inactive; Inactive; Inactive; Inactive; Active;
probability probability 0.99 probability 0.99 probability probability 0.98
0.98 0.99
Mutagenicity Inactive; Inactive; Inactive; Inactive; Inactive;
probability probability 0.61 probability 0.60 probability probability 0.69
0.53 0.60
Cytotoxicity Inactive; Inactive; Inactive; Inactive; Inactive;
probability probability 0.84 probability 0.85 probability probability 0.63
0.82 0.89

pkCSM
Intestinal 100 76.866 77.7 78.324 93.184
absorption
(human) (%
absorbed
Excretion (total 0.722 0.655 0.649 0.723 0.601
clearance) (log
ml/min/kg)
Max. tolerated 0.307 0.284 0.318 0.283 0.957
dose (human) (log
mg/kg/day)
Oral Rat Acute 2.49 2.485 2.489 2.485 2.84
Toxicity (LD50)
(mol/kg)