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Research Article | DOI: https://doi.org/10.31579/2767-7370/054
1 Department of Pharmacy, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, Chhattisgarh, 495009, India.
2 Drug Discovery and Research Laboratory Department of Pharmacy, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, Chhattisgarh, 495009, India
*Corresponding Author: Aman Naskarand Sanmati K. Jain, Drug Discovery and Research Laboratory Department of Pharmacy, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, Chhattisgarh, 495009, India
Citation: Dipti Pal, Smita Suthar, Aman N. Sanmati K. Jain, (2023). Design of p-methylphenyl Bioisosteres of Celecoxib as Selective COX-II Inhibitors Using Bioisosteric Approach, J New Medical Innovations and Research, 4(5); DOI:10.31579/2767-7370/054
Copyright: © 2023, Aman Naskarand Sanmati K. Jain. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 03 August 2023 | Accepted: 11 August 2023 | Published: 18 August 2023
Keywords: bioisosteric approach; celecoxib; p-methylphenyl; cox-ii inhibitors; computational tool; molopt
In present study, a bioisosteric approach was employed to design analogues of celecoxib, a selective COX-II inhibitor and non-steroidal anti-inflammatory drug. The p-methylphenyl group in celecoxib was targeted for bioisosteric replacement in order to develop newer molecules with reduced adverse effects. A total of 70 p-methylphenyl bioisosteres were generated using the MolOpt tool, including aryl halides, heteroaryl groups, hydrocarbons, and other functional groups. The newly designed analogues were evaluated for their medicinal properties, pharmacokinetic parameters, and toxicity using computational tools such as ADMETLab 2.0 and pkCSM. The results showed that 48 analogues exhibited good drug-likeness based on QED values and all obeys the Lipinski rule, and compound 062 (ethyl 1-(4-sulfamoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate) was identified as a novel and promising candidate based on its QED and MCE-18 scores. Furthermore, compound 065 (4-[5-(oxan-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzene-1-sulfonamide) demonstrated lower hepatotoxicity and respiratory toxicity compared to celecoxib. These findings highlight the potential of bioisosteric modifications in designing safer analogues of celecoxib with improved pharmacological properties. Compound 065, in particular, shows promise for further development as a potential anti-inflammatory drug with reduced adverse effects.
Inflammation is a complicated process that happens when tissues are harmed by a variety of things, such as noxious substances (such as bacteria or viruses), physical trauma, toxins, heat, or other causes. There are two main types of inflammation: acute inflammation and chronic inflammation. Acute inflammation is the primary type and acts as the host's essential immune response to remove unwanted stimuli and encourage tissue healing. Acute inflammation is a quick inflammatory response that occurs in the short term. Its goal is to neutralise and eradicate the cause of tissue damage while starting the healing process. Contrarily, chronic inflammation is a response that lasts for weeks, months, or even years. It involves sustained immune cell activation and ongoing production of inflammatory chemicals. Chronic inflammation is frequently accompanied by underlying diseases such autoimmune disorders, recurrent infections, or protracted contact with irritants. The phospholipase A2 pathway is important for the development of inflammation. By preventing the synthesis of leukotrienes and prostaglandins (PGs), two pro-inflammatory chemicals, steroids and nonsteroidal anti-inflammatory medications (NSAIDs) reduce inflammation. These medications block the phospholipase A2 pathway's enzyme activity, which lowers the generation of these inflammatory mediators and reduces inflammation. The cyclooxygenase (COX) enzymes are the molecular targets of all NSAIDs. In several organs, including platelets, kidneys, and the gastrointestinal (GI) tract, COX-1 is a constitutively expressed isoform. It contributes to keeping the GI tract and kidneys in a state of equilibrium.
Chemically, celecoxib is known as 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzene sulphonamide. It is an insoluble crystalline powder that dissolves in organic solvents like ethanol and methanol but is almost insoluble in water. Celecoxib has the chemical formula C17H14F3N3O2S and a molecular weight of 381.37 grams per mole. Celecoxib is made up of a pyrazole ring that is joined to a phenyl ring by a sulphonamide group. A trifluoromethyl group (CF3) and a methyl group (CH3) are also carried by the phenyl ring in two more positions. Celecoxib's distinctive pharmacological qualities, such as its selective inhibition of the COX-II enzyme, are a result of these structural characteristics. It is frequently used to treat acute pain, menstrual cramps, and illnesses like arthritis that cause discomfort and inflammation. Celecoxib is a type of COX-II inhibitor that particularly targets the cyclooxygenase-II (COX-II) enzyme, which is necessary for the creation of prostaglandins, which are inflammatory, painful, and fever-inducing chemicals. Celecoxib reduces the generation of prostaglandins that cause inflammation by specifically decreasing COX-II, which lowers pain and swelling. When compared to conventional NSAIDs, celecoxib offers the benefit of having a lower potential for gastrointestinal adverse effects such bleeding and stomach ulcers. This is due to the fact that COX-II inhibitors only target COX-II and spare COX-I, an enzyme that is constitutively produced and necessary for maintaining the stomach and intestines' protective lining. It's crucial to remember that gastrointestinal adverse effects can still happen even with this lower risk, particularly with prolonged or high-dose celecoxib treatment.
Celecoxib has undergone bioisoteric modification. This method substitutes existing groups that produce similar biological properties with substituents or groups with similar chemical or physical properties. The replacement of one or more atoms, groups, or fragments in a molecule with another that has equivalent physical or chemical properties is commonly referred to as a "bioisosteric approach" in drug design. Through structural modification, a drug's biological activity, pharmacokinetics, or physicochemical qualities are intended to be preserved or enhanced. The substituent or group that is switched out during this procedure is referred to as a "bioisostere." Bioisosteric substitutions can be used to achieve a variety of objectives in drug design, including boosting potency, enhancing selectivity, lowering toxicity, boosting metabolic stability, optimising solubility, or modifying other drug-like features. By replacing a specific moiety with a bioisostere, it is possible to maintain the desired interactions with the target biomolecule while altering other aspects of the molecule.
Bioisosteric replacements can be classified into different types based on the nature of the substituent being exchanged. Some common examples include:
The required pharmacological efficacy, target binding interactions, metabolic pathways, and potential off-target effects must all be carefully taken into account when choosing the right bioisosteres. To aid in the rational design and choice of bioisosteric replacements, computational approaches, structure-activity relationship (SAR) analyses, and medicinal chemistry knowledge are frequently used. The optimisation of drug candidates by adjusting their properties while maintaining the required biological effects is made possible by bioisosteric techniques, which can be useful tools in drug discovery and development. The effective use of bioisosteres, it is crucial to remember, depends on a thorough comprehension of the underlying molecular interactions and possible effects on therapeutic efficacy and safety.
In the current study, the p-methylphenyl group in celecoxib molecules has been treated using a bioisosteric technique in order to create newer analogues with less adverse effects, such as liver damage and cardiovascular side effects, which are important contributors to drug withdrawal. Therefore, in order to create comparatively safe molecules, celecoxib p-methylphenyl bioisosteres are designed utilising the bioisosteric technique.
Celecoxib acts as a selective COX-II inhibitor and oral non-steroidal anti-inflammatory drug, it may be hepatotoxic on the long-term use, special precaution may be taken and liver function test is being suggested periodically.
Celecoxib’s p-methylphenylbioisosteres were designed using MolOpt and the molecular structure of newly designed analogues and their properties is listed in Table 1. Pharmacokinetic and toxicity (ADMET) property of newly designed analogue are envisaged by using ADMETLab 2.0 and pkCSM.
3.1 p-methylphenyl Bioisoteres of celecoxib:
MolOpt tool was employed for in-silico design of newer analogues of celecoxib by consideringp-methylphenylgroup for bioisosteric replacement.
3.2 Pharmacokinetic and ADMET properties prediction:
Various absorption, distribution, metabolism, excretion and toxicity (ADMET) properties were calculated by using ADMETLab 2.0. In this study, Human Intestinal Absorption property (HIA in %) were calculated by using pkCSM.
4.1 Bioisosteres of p-methylphenyl group of celecoxib:
Total 70 p-methylphenyl bioisosteres analogues of celecoxib were generated i.e., Aryl halide, Aryl and substituted Aryl group, Heteroaryl group, Non aromatic heterocyclic group, Hydrocarbon, Aryl ether, Phenolic, Ester, Alcohol, Halogenated aryl, Cycloalkyl, Amide etc., shown in Figure 2 using MolOpt tool. Bioisosteres and their properties are shown in Table 1.
Figure 2: p-methylphenyl bioisostere analogues of celecoxib.
| S. No | Entry No | Structure | Type of bioisosters | MW | nHA | nHD | nRot | TPSA | LogS | LogP |
| 1. | Celecoxib |  | p-methylphenyl | 381.08
| 5 | 2 | 4
| 77.98
| -5.289
| 3.528
|
| 2. | 000 |  | Aryl halide | 401.02 | 5 | 2 | 4 | 77.98 | -5.594 | 3.752 |
| 3. | 001 |  | Aryl halide | 401.02 | 5 | 2 | 4 | 77.98 | -5.302 | 3.441 |
| 4. | 002 |  | Aryl halide | 385.05 | 5 | 2 | 4 | 77.98 | -5.117 | 3.249 |
| 5. | 003 |  | Aryl halide | 385.05 | 5 | 2 | 4 | 77.98 | -5.01 | 3.094 |
| 6. | 005 |  | Benzyl | 381.08 | 5 | 2 | 5 | 77.98 | -4.438 | 3.028 |
| 7. | 006 |  | Cycloalkyl | 373.11 | 5 | 2 | 4 | 77.98 | -5.147 | 3.586 |
| 8. | 007 |  | Heteroaryl | 368.06 | 6 | 2 | 4 | 90.87 | -3.372 | 1.977 |
| 9. | 008 |  | Heteroaryl | 368.06 | 6 | 2 | 4 | 90.87 | -3.618 | 2.062 |
| 10. | 009 |  | Heteroaryl | 368.06 | 6 | 2 | 4 | 90.87 | -4.128 | 2.213 |
| 11. | 010 |  | Phenolic | 383.06 | 6 | 3 | 4 | 98.21 | -3.949 | 2.767 |
| 12. | 011 |  | Heteroaryl | 411.05 | 7 | 2 | 4 | 96.44 | -5.423 | 3.044 |
| 13. | 013 |  | Phenolic | 383.06 | 6 | 3 | 4 | 98.21 | -4.187 | 2.938 |
| 14. | 014
|  | Aryl halide | 403.04 | 5 | 2 | 4 | 77.98 | -5.432 | 3.404 |
| 15. | 015
|  | Aryl halide | 403.04 | 5 | 2 | 4 | 77.98 | -5.235 | 3.215 |
| 16. | 017 |  | Substituted aryl | 395.09 | 5 | 2 | 6 | 77.98 | -4.735 | 3.32 |
| 17. | 018 |  | Aryl halide | 403.04 | 5 | 2 | 4 | 77.98 | -5.261 | 3.328 |
| 18. | 020 |  | Substituted Aryl | 393.08 | 5 | 2 | 5 | 77.98 | -4.886 | 3.53 |
| 19. | 021 |  | Aryl halide | 419.01 | 5 | 2 | 4 | 77.98 | -5.997 | 3.826 |
| 20. | 022 |  | Aryl halide | 403.04 | 5 | 2 | 4 | 77.98 | -5.608 | 3.064 |
| 21. | 023 |  | Substituted Aryl | 395.09 | 5 | 2 | 5 | 77.98 | -5.367 | 3.734 |
| 22. | 025 |  | Aryl halide | 415.04 | 5 | 2 | 5 | 77.98 | -5.092 | 3.684 |
| 23. | 027 |  | Hydrocarbon | 361.11 | 5 | 2 | 7 | 77.98 | -4.73 | 3.495 |
| 24. | 028 |  | Substituted Aryl | 395.09 | 5 | 2 | 5 | 77.98 | -5.802 | 3.89 |
| 25. | 030 |  | Aryl halide | 403.04 | 5 | 2 | 4 | 77.98 | -5.32 | 3.252 |
| 26. | 031 |  | Aryl ether | 411.09 | 6 | 2 | 6 | 87.21 | -5.03 | 3.172 |
| 27. | 032 |  | Halogenated aryl group | 399.07 | 5 | 2 | 5 | 77.98 | -4.636 | 3.12 |
| 28. | 035 |  | Cycloalkyl | 387.12 | 5 | 2 | 4 | 77.98 | -5.55 | 4.08 |
| 29. | 036 |  | Aryl halide | 403.04 | 5 | 2 | 4 | 77.98 | -5.346 | 3.252 |
| 30. | 037 |  | Adamantinyl | 425.14 | 5 | 2 | 4 | 77.98 | -5.55 | 4.329 |
| 31. | 038 |  | Non-aromatic heterocyclic | 425.07 | 7 | 2 | 4 | 96.44 | -5.489 | 2.965 |
| 32. | 039 |  | Heteroaryl | 369.05 | 7 | 2 | 4 | 103.76 | -3.217 | 1.044 |
| 33. | 041 |  | Hydrocarbon | 375.12 | 5 | 2 | 8 | 77.98 | -5.124 | 3.919 |
| 34. | 042 |  | Benzamide | 410.07 | 7 | 4 | 5 | 121.07 | -4.436 | 2.148 |
| 35. | 043 |  | Heteroaryl | 369.05 | 7 | 2 | 4 | 103.76 | -3.053 | 1.517 |
| 36. | 045 |  | Aryl ether | 411.09 | 6 | 2 | 6 | 87.21 | -5.303 | 3.576 |
| 37. | 049 |  | Heteroaryl | 369.05 | 7 | 2 | 4 | 103.76 | -2.955 | 1.261 |
| 38. | 051 |  | Aryl ether | 397.07 | 6 | 2 | 6 | 87.21 | -4.08 | 2.535 |
| 39. | 052 |  | Hydrocarbon | 331.06 | 5 | 2 | 5 | 77.98 | -3.396 | 2.269 |
| 40. | 054 |  | Alcohol | 335.06 | 6 | 3 | 5 | 98.21 | -2.326 | 0.831 |
| 41. | 058 |  | Halogenated aryl | 415.04 | 5 | 2 | 5 | 77.98 | -4.977 | 3.714 |
| 42. | 059 |  | Heteroaryl | 402.02 | 6 | 2 | 4 | 90.87 | -4.451 | 2.658 |
| 43. | 060 |  | Heteroaryl | 371.06 | 6 | 2 | 5 | 91.12 | -3.838 | 2.419 |
| 44. | 061 |  | Aryl ether | 383.06 | 6 | 2 | 5 | 87.21 | -4.606 | 2.863 |
| 45. | 062 |  | Ester | 363.05 | 7 | 2 | 6 | 104.28 | -3.493 | 2.021 |
| 46. | 065 |  | Non-aromatic heterocyclic | 375.09 | 6 | 2 | 4 | 87.21 | -3.513 | 1.908 |
| 47. | 067 |  | Heteroaryl | 402.02 | 6 | 2 | 4 | 90.87 | -5.119 | 3.088 |
| 48. | 069 |  | Non-aromatic heterocyclic | 376.08 | 7 | 2 | 4 | 90.45 | -3.876 | 1.502 |
MW (Molecular weight), nHA (Number of hydrogen bond acceptor), nHD (Number of hydrogen bond acceptor), nRot (Number of rotatable bonds), TPSA (Topological polar surface area), logP (The logarithm of aqueous solubility value), logS (The logarithm of aqueous solubility value)
Table 1: p-methylphenyl bioisostere analogues of celecoxib
4.2 Pharmacokinetic (ADME) and Toxicity properties prediction:
Medicinal properties, Pharmacokinetic properties like absorption, distribution, metabolism, excretion (ADME) and toxicity properties were calculated by using pkCSM and ADMElab2.0. Medicinal Properties of the analogues are shown in Table 2 and among 70p-methylphenyl bioisosteres analogues in which all obeys the Lipinski, Pfizer, and golden triangle rule48 compounds showing greater than >0.67 QED value (measure of drug-likeness) indicates that these compounds are attractive but compound 000, 015, 017, 025, 030, 035, 037, 038, 0.45, 058 does not obeys the GSK rule. Compound 006, 011, 035, 037, 038, 065, and 069 having ≥45 MCE-18 score (measure the molecules effectively by novelty in terms of their cumulative sp3 complexity) was found novel, follows the current trend observed in medicinal chemistry.
| S. No. | Entry No. | QED | Synth | Fsp3 | MCE-18 | Lipinski | Pfizer | GSK | Golden Triangle |
| 1. | 000 | 0.723 | 2.21 | 0.062 | 22 | Accepted | Accepted | Rejected | Accepted |
| 2. | 005 | 0.754 | 2.253 | 0.118 | 21 | Accepted | Accepted | Accepted | Accepted |
| 3. | 006 | 0.893 | 2.366 | 0.438 | 52.957 | Accepted | Accepted | Accepted | Accepted |
| 4. | 011 | 0.715 | 2.375 | 0.118 | 54.737 | Accepted | Accepted | Rejected | Accepted |
| 5. | 013 | 0.727 | 2.299 | 0.062 | 22 | Accepted | Accepted | Accepted | Accepted |
| 6. | 015 | 0.68 | 2.33 | 0.062 | 23 | Accepted | Accepted | Rejected | Accepted |
| 7. | 017 | 0.72 | 2.242 | 0.167 | 21 | Accepted | Accepted | Accepted | Accepted |
| 8. | 025 | 0.704 | 2.319 | 0.118 | 22 | Accepted | Accepted | Rejected | Accepted |
| 9. | 027 | 0.802 | 2.322 | 0.4 | 17 | Accepted | Accepted | Accepted | Accepted |
| 10. | 028 | 0.731 | 2.24 | 0.167 | 22 | Accepted | Accepted | Accepted | Accepted |
| 11. | 030 | 0.68 | 2.346 | 0.062 | 23 | Accepted | Accepted | Rejected | Accepted |
| 12. | 032 | 0.684 | 2.324 | 0.118 | 22 | Accepted | Accepted | Accepted | Accepted |
| 13. | 035 | 0.81 | 2.371 | 0.471 | 53.76 | Accepted | Accepted | Rejected | Accepted |
| 14. | 037 | 0.807 | 3.88 | 0.55 | 84.645 | Accepted | Accepted | Rejected | Accepted |
| 15. | 038 | 0.696 | 2.404 | 0.167 | 56.952 | Accepted | Accepted | Rejected | Accepted |
| 16. | 041 | 0.75 | 2.331 | 0.438 | 17 | Accepted | Accepted | Accepted | Accepted |
| 17. | 044 | 0.707 | 2.291 | 0.118 | 22 | Accepted | Accepted | Accepted | Accepted |
| 18. | 045 | 0.695 | 2.241 | 0.167 | 22 | Accepted | Accepted | Rejected | Accepted |
| 19. | 051 | 0.717 | 2.228 | 0.118 | 21 | Accepted | Accepted | Accepted | Accepted |
| 20. | 054 | 0.873 | 2.418 | 0.25 | 17 | Accepted | Accepted | Accepted | Accepted |
| 21. | 058 | 0.704 | 2.376 | 0.118 | 22 | Accepted | Accepted | Rejected | Accepted |
| 22. | 060 | 0.763 | 2.561 | 0.133 | 21 | Accepted | Accepted | Accepted | Accepted |
| 23. | 062 | 0.833 | 2.26 | 0.231 | 18 | Accepted | Accepted | Accepted | Accepted |
| 24. | 065 | 0.893 | 2.513 | 0.4 | 52 | Accepted | Accepted | Accepted | Accepted |
| 25. | 069 | 0.874 | 2.457 | 0.357 | 50.842 | Accepted | Accepted | Accepted | Accepted |
| 26. | Celecoxib | 0.754 | 2.144 | 0.118 | 22 | Accepted | Accepted | Accepted | Accepted |
QED (A measure of drug-likeness based on the concept of desirability), SAscore (Synthetic accessibility score), Fsp3 (The number of sp3 hybridized carbons/total carbon count), MCE-18 (Medicinal chemistry evolution in 2018).
Table 2: Medicinal Properties of selected Analogues
Compound having value more than >0.7 indicating toxicity like hepatotoxicity (H-HT), cardiovascular toxicity (hERG), and respiratory toxicity was not included in the Table 3-5. Absorption properties (Caco-2, MDCK, and HIA) and distribution properties (Plasma Protein Binding, Volume of Distribution, Blood-Brain Barrier and Fu) are shown in Table-3. All the analogues have proper caco-2 permeability, high passive MDCK permeability and human intestinal absorption more than 90%, indicating that these compounds may be orally effective. Human Intestinal Absorption property (HIA in %) was calculated by using pkCSM, shown in Table 3.
| S. No. | Entry No. | Caco-2 | MDCK | HIA (%) | BBB | PPB | VDss |
| 1. | 000 | -4.72 | 1.76E-05 | 91.511 | 0.503 | 96.22% | 1.382 |
| 2. | 005 | -4.838 | 3.38E-05 | 91.976 | 0.702 | 93.12% | 0.955 |
| 3. | 013 | -4.98 | 1.90E-05 | 93.182 | 0.17 | 94.27% | 0.955 |
| 4. | 015 | -4.645 | 2.74E-05 | 91.598 | 0.412 | 94.30% | 0.906 |
| 5. | 017 | -4.774 | 2.17E-05 | 93.088 | 0.793 | 94.88% | 1.128 |
| 6. | 025 | -4.782 | 2.24E-05 | 92.152 | 0.502 | 95.95% | 0.923 |
| 7. | 027 | -4.689 | 2.97E-05 | 91.084 | 0.839 | 92.00% | 2.031 |
| 8. | 028 | -4.679 | 2.24E-05 | 92.742 | 0.563 | 95.38% | 1.4 |
| 9. | 030 | -4.649 | 2.77E-05 | 92.763 | 0.37 | 94.57% | 0.859 |
| 10. | 032 | -4.802 | 3.23E-05 | 93.248 | 0.495 | 94.43% | 0.844 |
| 11. | 041 | -4.71 | 2.68E-05 | 90.728 | 0.805 | 94.18% | 2.136 |
| 12. | 044 | -5.045 | 1.57E-05 | 94.951 | 0.774 | 84.23% | 1.179 |
| 13. | 045 | -4.758 | 2.10E-05 | 92.718 | 0.297 | 95.51% | 1.421 |
| 14. | 051 | -4.941 | 2.93E-05 | 91.41 | 0.401 | 94.94% | 1.197 |
| 15. | 054 | -4.866 | 2.38E-05 | 81.173 | 0.979 | 44.57% | 1.354 |
| 16. | 058 | -4.737 | 3.65E-05 | 92.923 | 0.686 | 95.87% | 0.999 |
| 17. | 060 | -4.849 | 3.21E-05 | 94.991 | 0.544 | 87.34% | 1.047 |
| 18. | 062 | -4.939 | 3.38E-05 | 83.669 | 0.858 | 81.65% | 0.866 |
| 19. | 065 | -4.873 | 2.67E-05 | 93.407 | 0.895 | 63.82% | 1.41 |
| 20. | Celecoxib | -4.767 | 2.30E-05 | 92.995 | 0.586 | 94.96% | 1.105 |
Caco-2 (The human colon adenocarcinoma cell lines), MDCK (Madin−Darby Canine Kidney cells) and >2 x 10-6cm/s indicates excellent, HIA (Human Intestinal Absorption), (PPB) Plasma protein binding, BBB (blood–brain barrier), VD (Volume Distribution), Fu (The fraction unbound in plasms).*Property calculated by pkCSM.
Table 3: Absorption and Distribution Profile of the selected Analogues
Metabolism (CYP1A2-inh and sub, CYP2C19-inh and sub, CYP2C9-inh and sub, CYP2D6-inh and sub, CYP3A4-inh and sub) were calculated by using pkCSM and excretion (CL and T1/2) properties are shown in Table-4 and compounds having value <5>S. No. Entry No. CYP1A2 CYP2C9 CYP2D6 CYP3A4 CL T1/2 1. 000 YES YES NO NO 1.034 0.027 2. 005 YES NO NO NO 1.115 0.07 3. 013 YES YES NO YES 0.959 0.049 4. 015 YES YES NO YES 1.242 0.014 5. 017 NO YES NO YES 1.06 0.042 6. 025 YES YES NO YES 1.379 0.037 7. 027 YES YES NO NO 1.315 0.043 8. 028 YES YES NO YES 0.958 0.039 9. 030 YES YES NO NO 1.245 0.014 10. 032 YES YES NO YES 1.309 0.032 11. 041 YES YES NO NO 1.342 0.036 12. 044 YES NO NO YES 0.93 0.101 13. 045 YES YES NO YES 1.161 0.03 14. 051 NO YES NO NO 1.019 0.077 15. 054 NO NO NO NO 1.28 0.169 16. 058 YES YES NO YES 1.553 0.036 17. 060 YES NO NO NO 1.163 0.095 18. 062 YES NO NO NO 1.401 0.051 19. 065 NO NO NO NO 1.123 0.048 20. Celecoxib YES YES NO YES 0.992 0.029
Human cytochrome P450 (five isozymes––1A2, 3A4, 2C9, 2C19 and 2D6), CL (The clearance of a drug), T1/2 (The half-life of a drug)
Table 4: Metabolism and Excretion Profile of selected Analogues
Toxicity profile (hERG, H-HT, DILI, Ames, ROA, Carcinogenicity, Respiratory toxicity) of selected analogue are shown in Table 5 and compound 062 are found less hepatotoxic and compound 005, 017, 025, 032, 051, 054, 058, 062 are found less respiratory toxic which is the common reason of market withdrawal of drugs. According to this data the compound 062 are less hepatotoxic and respiratory toxic than the lead compound.
| S. No. | Entry No. | hERG | H-HT | DILI | Ames | ROA | Carcinogenicity | Respiratory toxicity |
| 1. | 000 | 0.174 | 0.615 | 0.991 | 0.009 | 0.73 | 0.088 | 0.582 |
| 2. | 005 | 0.053 | 0.466 | 0.992 | 0.025 | 0.476 | 0.127 | 0.211 |
| 3. | 013 | 0.03 | 0.552 | 0.992 | 0.025 | 0.741 | 0.127 | 0.655 |
| 4. | 015 | 0.134 | 0.698 | 0.991 | 0.025 | 0.671 | 0.169 | 0.663 |
| 5. | 017 | 0.156 | 0.64 | 0.988 | 0.023 | 0.722 | 0.117 | 0.154 |
| 6. | 025 | 0.117 | 0.467 | 0.992 | 0.016 | 0.497 | 0.129 | 0.147 |
| 7. | 027 | 0.06 | 0.393 | 0.989 | 0.011 | 0.604 | 0.084 | 0.635 |
| 8. | 028 | 0.204 | 0.588 | 0.99 | 0.014 | 0.729 | 0.078 | 0.53 |
| 9. | 030 | 0.165 | 0.683 | 0.99 | 0.02 | 0.665 | 0.146 | 0.644 |
| 10. | 032 | 0.101 | 0.48 | 0.992 | 0.027 | 0.337 | 0.185 | 0.267 |
| 11. | 041 | 0.071 | 0.383 | 0.988 | 0.011 | 0.581 | 0.085 | 0.698 |
| 12. | 044 | 0.107 | 0.436 | 0.992 | 0.013 | 0.702 | 0.066 | 0.344 |
| 13. | 045 | 0.165 | 0.491 | 0.991 | 0.017 | 0.557 | 0.12 | 0.408 |
| 14. | 051 | 0.094 | 0.6 | 0.993 | 0.037 | 0.578 | 0.268 | 0.27 |
| 15. | 054 | 0.029 | 0.443 | 0.991 | 0.019 | 0.568 | 0.114 | 0.186 |
| 16. | 058 | 0.051 | 0.637 | 0.993 | 0.016 | 0.589 | 0.138 | 0.222 |
| 17. | 060 | 0.042 | 0.405 | 0.991 | 0.02 | 0.645 | 0.166 | 0.376 |
| 18. | 062 | 0.031 | 0.109 | 0.991 | 0.006 | 0.453 | 0.088 | 0.258 |
| 19. | 065 | 0.146 | 0.663 | 0.989 | 0.037 | 0.934 | 0.248 | 0.424 |
| 20. | Celecoxib | 0.105 | 0.641 | 0.991 | 0.016 | 0.771 | 0.139 | 0.584 |
H-HT (The human hepatotoxicity), DILI (Drug-induced liver injury), hERG Blockers (Human ether-a-go-go related gene), Ames (test for mutagenicity), ROA (Rat Oral Acute Toxicity)
Table 5: Toxicity Profile of selected Analogues
Many of the celecoxib analogues were designed using bioisosteric approach and their medicinal, pharmacokinetic and toxicity properties were calculated by using in-silico methods. The results indicate 70 analogues are generated by the p-methylphenyl celecoxib bioisosteres as anti-inflammatory drug. Each analogue was evaluated based on QED value (eight physicochemical properties, including MW, log P, HBA, HBA, PSA, number of rotatable bonds, number of aromatic rings, and the presence of undesirable functional groups) and 48 analogues were selected having QED values of 0.67 or greater, indicating good drug-like properties. The compound 062 (ethyl 1-(4-sulfamoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate) was found novel based on QED and MCE-18 score, follows the current trend observed in medicinal chemistry and one of the analogue compounds 065 (4-[5-(oxan-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzene-1-sulfonamide) found to have low hepatotoxicity and respiratory toxicity compared to celecoxib, making it a promising candidate for further development.
Acknowledgement
The authors are indebted to the Head, Department of Pharmacy, Guru Ghasidas Vishwavidyalaya, Bilaspur (C.G) for providing necessary facilities.
Author Contributions: All authors equally contributed.
Conflict of Interest: No conflict of interest
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