AUCTORES
Globalize your Research
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
Clearly Auctoresonline and particularly Psychology and Mental Health Care Journal is dedicated to improving health care services for individuals and populations. The editorial boards' ability to efficiently recognize and share the global importance of health literacy with a variety of stakeholders. Auctoresonline publishing platform can be used to facilitate of optimal client-based services and should be added to health care professionals' repertoire of evidence-based health care resources.
Journal of Clinical Cardiology and Cardiovascular Intervention The submission and review process was adequate. However I think that the publication total value should have been enlightened in early fases. Thank you for all.
Journal of Women Health Care and Issues By the present mail, I want to say thank to you and tour colleagues for facilitating my published article. Specially thank you for the peer review process, support from the editorial office. I appreciate positively the quality of your journal.
Journal of Clinical Research and Reports I would be very delighted to submit my testimonial regarding the reviewer board and the editorial office. The reviewer board were accurate and helpful regarding any modifications for my manuscript. And the editorial office were very helpful and supportive in contacting and monitoring with any update and offering help. It was my pleasure to contribute with your promising Journal and I am looking forward for more collaboration.
We would like to thank the Journal of Thoracic Disease and Cardiothoracic Surgery because of the services they provided us for our articles. The peer-review process was done in a very excellent time manner, and the opinions of the reviewers helped us to improve our manuscript further. The editorial office had an outstanding correspondence with us and guided us in many ways. During a hard time of the pandemic that is affecting every one of us tremendously, the editorial office helped us make everything easier for publishing scientific work. Hope for a more scientific relationship with your Journal.
The peer-review process which consisted high quality queries on the paper. I did answer six reviewers’ questions and comments before the paper was accepted. The support from the editorial office is excellent.
Journal of Neuroscience and Neurological Surgery. I had the experience of publishing a research article recently. The whole process was simple from submission to publication. The reviewers made specific and valuable recommendations and corrections that improved the quality of my publication. I strongly recommend this Journal.
Dr. Katarzyna Byczkowska My testimonial covering: "The peer review process is quick and effective. The support from the editorial office is very professional and friendly. Quality of the Clinical Cardiology and Cardiovascular Interventions is scientific and publishes ground-breaking research on cardiology that is useful for other professionals in the field.
Thank you most sincerely, with regard to the support you have given in relation to the reviewing process and the processing of my article entitled "Large Cell Neuroendocrine Carcinoma of The Prostate Gland: A Review and Update" for publication in your esteemed Journal, Journal of Cancer Research and Cellular Therapeutics". The editorial team has been very supportive.
Testimony of Journal of Clinical Otorhinolaryngology: work with your Reviews has been a educational and constructive experience. The editorial office were very helpful and supportive. It was a pleasure to contribute to your Journal.
Dr. Bernard Terkimbi Utoo, I am happy to publish my scientific work in Journal of Women Health Care and Issues (JWHCI). The manuscript submission was seamless and peer review process was top notch. I was amazed that 4 reviewers worked on the manuscript which made it a highly technical, standard and excellent quality paper. I appreciate the format and consideration for the APC as well as the speed of publication. It is my pleasure to continue with this scientific relationship with the esteem JWHCI.
This is an acknowledgment for peer reviewers, editorial board of Journal of Clinical Research and Reports. They show a lot of consideration for us as publishers for our research article “Evaluation of the different factors associated with side effects of COVID-19 vaccination on medical students, Mutah university, Al-Karak, Jordan”, in a very professional and easy way. This journal is one of outstanding medical journal.
Dear Hao Jiang, to Journal of Nutrition and Food Processing We greatly appreciate the efficient, professional and rapid processing of our paper by your team. If there is anything else we should do, please do not hesitate to let us know. On behalf of my co-authors, we would like to express our great appreciation to editor and reviewers.
As an author who has recently published in the journal "Brain and Neurological Disorders". I am delighted to provide a testimonial on the peer review process, editorial office support, and the overall quality of the journal. The peer review process at Brain and Neurological Disorders is rigorous and meticulous, ensuring that only high-quality, evidence-based research is published. The reviewers are experts in their fields, and their comments and suggestions were constructive and helped improve the quality of my manuscript. The review process was timely and efficient, with clear communication from the editorial office at each stage. The support from the editorial office was exceptional throughout the entire process. The editorial staff was responsive, professional, and always willing to help. They provided valuable guidance on formatting, structure, and ethical considerations, making the submission process seamless. Moreover, they kept me informed about the status of my manuscript and provided timely updates, which made the process less stressful. The journal Brain and Neurological Disorders is of the highest quality, with a strong focus on publishing cutting-edge research in the field of neurology. The articles published in this journal are well-researched, rigorously peer-reviewed, and written by experts in the field. The journal maintains high standards, ensuring that readers are provided with the most up-to-date and reliable information on brain and neurological disorders. In conclusion, I had a wonderful experience publishing in Brain and Neurological Disorders. The peer review process was thorough, the editorial office provided exceptional support, and the journal's quality is second to none. I would highly recommend this journal to any researcher working in the field of neurology and brain disorders.
Dear Agrippa Hilda, Journal of Neuroscience and Neurological Surgery, Editorial Coordinator, I trust this message finds you well. I want to extend my appreciation for considering my article for publication in your esteemed journal. I am pleased to provide a testimonial regarding the peer review process and the support received from your editorial office. The peer review process for my paper was carried out in a highly professional and thorough manner. The feedback and comments provided by the authors were constructive and very useful in improving the quality of the manuscript. This rigorous assessment process undoubtedly contributes to the high standards maintained by your journal.
International Journal of Clinical Case Reports and Reviews. I strongly recommend to consider submitting your work to this high-quality journal. The support and availability of the Editorial staff is outstanding and the review process was both efficient and rigorous.
Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.
Dear Erica Kelsey, Editorial Coordinator of Cancer Research and Cellular Therapeutics Our team is very satisfied with the processing of our paper by your journal. That was fast, efficient, rigorous, but without unnecessary complications. We appreciated the very short time between the submission of the paper and its publication on line on your site.
I am very glad to say that the peer review process is very successful and fast and support from the Editorial Office. Therefore, I would like to continue our scientific relationship for a long time. And I especially thank you for your kindly attention towards my article. Have a good day!
"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".
I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.
We are grateful for this opportunity to provide a glowing recommendation to the Journal of Psychiatry and Psychotherapy. We found that the editorial team were very supportive, helpful, kept us abreast of timelines and over all very professional in nature. The peer review process was rigorous, efficient and constructive that really enhanced our article submission. The experience with this journal remains one of our best ever and we look forward to providing future submissions in the near future.
I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.
I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.
I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.
Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.
“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.
Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.
Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.
Clinical Cardiology and Cardiovascular Interventions, we deeply appreciate the interest shown in our work and its publication. It has been a true pleasure to collaborate with you. The peer review process, as well as the support provided by the editorial office, have been exceptional, and the quality of the journal is very high, which was a determining factor in our decision to publish with you.
The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews journal clinically in the future time.
Clinical Cardiology and Cardiovascular Interventions, I would like to express my sincerest gratitude for the trust placed in our team for the publication in your journal. It has been a true pleasure to collaborate with you on this project. I am pleased to inform you that both the peer review process and the attention from the editorial coordination have been excellent. Your team has worked with dedication and professionalism to ensure that your publication meets the highest standards of quality. We are confident that this collaboration will result in mutual success, and we are eager to see the fruits of this shared effort.
