Design of p-methylphenyl Bioisosteres of Celecoxib as Selective COX-II Inhibitors Using Bioisosteric Approach

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Research Article | DOI: https://doi.org/10.31579/2767-7370/054

Design of p-methylphenyl Bioisosteres of Celecoxib as Selective COX-II Inhibitors Using Bioisosteric Approach

Dipti Pal ¹

Smita Suthar ¹

Aman Naskarand Sanmati K. Jain ^2*

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

Abstract

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.

Introduction

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:
Classical Bioisosteres: These involve substituting an atom or group with another that has similar size, shape, and charge distribution. For instance, replacing a hydrogen atom with a halogen atom (e.g., fluorine, chlorine) or an oxygen atom with a sulphur atom.
Nonclassical Bioisosteres: These involve more complex substitutions that may alter the electronic or steric properties of the molecule. Examples include replacing an amide group with an ester, an ester with a carbonate, or an aromatic ring with a bioisosteric heterocycle.
Bioisosteres for Functional Groups: This approach focuses on replacing a specific functional group with another that can mimic its chemical properties. For example, replacing a carboxylic acid (-COOH) with a bioisosteric sulfonic acid (-SO3H) or a primary amine (-NH2) with a bioisosteric hydroxamic acid (-C(O)NHOH).
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.

Material and Methods

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.

Results and Discussion

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

Conclusion

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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Dear Jessica, and the super professional team of the ‘Clinical Cardiology and Cardiovascular Interventions’ I am sincerely grateful to the coordinated work of the journal team for the no problem with the submission of my manuscript: “Cardiometabolic Disorders in A Pregnant Woman with Severe Preeclampsia on the Background of Morbid Obesity (Case Report).” The review process by 5 experts was fast, and the comments were professional, which made it more specific and academic, and the process of publication and presentation of the article was excellent. I recommend that my colleagues publish articles in this journal, and I am interested in further scientific cooperation. Sincerely and best wishes, Dr. Oleg Golyanovskiy.

Dr Oleg Golyanovski

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.

Virginia E. Koenig

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.

Delcio G Silva Junior

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.

Ziemlé Clément Méda

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.

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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.

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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.

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Orlando Villarreal

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.

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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.

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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.

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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.

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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.

Andreas Filippaios

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.

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Baheci Selen

"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".

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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.

Dr Griffith

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.

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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.

S Munshi

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.

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George Varvatsoulias

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.

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.

Khurram Arshad

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.

Gomez Barriga Maria Dolores

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.

Lin Shaw Chin

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.

Maria Dolores Gomez Barriga

Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, I hope this message finds you well. I want to express my utmost gratitude for your excellent work and for the dedication and speed in the publication process of my article titled "Navigating Innovation: Qualitative Insights on Using Technology for Health Education in Acute Coronary Syndrome Patients." I am very satisfied with the peer review process, the support from the editorial office, and the quality of the journal. I hope we can maintain our scientific relationship in the long term.

Dr Maria Dolores Gomez Barriga

Dear Monica Gissare, - Editorial Coordinator of Nutrition and Food Processing. ¨My testimony with you is truly professional, with a positive response regarding the follow-up of the article and its review, you took into account my qualities and the importance of the topic¨.

Dr Maria Regina Penchyna Nieto

Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, The review process for the article “The Handling of Anti-aggregants and Anticoagulants in the Oncologic Heart Patient Submitted to Surgery” was extremely rigorous and detailed. From the initial submission to the final acceptance, the editorial team at the “Journal of Clinical Cardiology and Cardiovascular Interventions” demonstrated a high level of professionalism and dedication. The reviewers provided constructive and detailed feedback, which was essential for improving the quality of our work. Communication was always clear and efficient, ensuring that all our questions were promptly addressed. The quality of the “Journal of Clinical Cardiology and Cardiovascular Interventions” is undeniable. It is a peer-reviewed, open-access publication dedicated exclusively to disseminating high-quality research in the field of clinical cardiology and cardiovascular interventions. The journal's impact factor is currently under evaluation, and it is indexed in reputable databases, which further reinforces its credibility and relevance in the scientific field. I highly recommend this journal to researchers looking for a reputable platform to publish their studies.

Dr Marcelo Flavio Gomes Jardim Filho

Dear Editorial Coordinator of the Journal of Nutrition and Food Processing! "I would like to thank the Journal of Nutrition and Food Processing for including and publishing my article. The peer review process was very quick, movement and precise. The Editorial Board has done an extremely conscientious job with much help, valuable comments and advices. I find the journal very valuable from a professional point of view, thank you very much for allowing me to be part of it and I would like to participate in the future!”

Zsuzsanna Bene

Dealing with The Journal of Neurology and Neurological Surgery was very smooth and comprehensive. The office staff took time to address my needs and the response from editors and the office was prompt and fair. I certainly hope to publish with this journal again.Their professionalism is apparent and more than satisfactory. Susan Weiner

Dr Susan Weiner

My Testimonial Covering as fellowing: Lin-Show Chin. 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.

Lin-Show Chin

My experience publishing in Psychology and Mental Health Care was exceptional. The peer review process was rigorous and constructive, with reviewers providing valuable insights that helped enhance the quality of our work. The editorial team was highly supportive and responsive, making the submission process smooth and efficient. The journal's commitment to high standards and academic rigor makes it a respected platform for quality research. I am grateful for the opportunity to publish in such a reputable journal.

Sonila Qirko

My experience publishing in International Journal of Clinical Case Reports and Reviews was exceptional. I Come forth to Provide a Testimonial Covering the Peer Review Process and the editorial office for the Professional and Impartial Evaluation of the Manuscript.

Luiz Sellmann

I would like to offer my testimony in the support. I have received through the peer review process and support the editorial office where they are to support young authors like me, encourage them to publish their work in your esteemed journals, and globalize and share knowledge globally. I really appreciate your journal, peer review, and editorial office.

Zhao Jia

Dear Agrippa Hilda- Editorial Coordinator of Journal of Neuroscience and Neurological Surgery, "The peer review process was very quick and of high quality, which can also be seen in the articles in the journal. The collaboration with the editorial office was very good."

Thomas Urban

I would like to express my sincere gratitude for the support and efficiency provided by the editorial office throughout the publication process of my article, “Delayed Vulvar Metastases from Rectal Carcinoma: A Case Report.” I greatly appreciate the assistance and guidance I received from your team, which made the entire process smooth and efficient. The peer review process was thorough and constructive, contributing to the overall quality of the final article. I am very grateful for the high level of professionalism and commitment shown by the editorial staff, and I look forward to maintaining a long-term collaboration with the International Journal of Clinical Case Reports and Reviews.

Cristina Berriozabal

To Dear Erin Aust, I would like to express my heartfelt appreciation for the opportunity to have my work published in this esteemed journal. The entire publication process was smooth and well-organized, and I am extremely satisfied with the final result. The Editorial Team demonstrated the utmost professionalism, providing prompt and insightful feedback throughout the review process. Their clear communication and constructive suggestions were invaluable in enhancing my manuscript, and their meticulous attention to detail and dedication to quality are truly commendable. Additionally, the support from the Editorial Office was exceptional. From the initial submission to the final publication, I was guided through every step of the process with great care and professionalism. The team's responsiveness and assistance made the entire experience both easy and stress-free. I am also deeply impressed by the quality and reputation of the journal. It is an honor to have my research featured in such a respected publication, and I am confident that it will make a meaningful contribution to the field.

Dr Tewodros Kassahun Tarekegn

"I am grateful for the opportunity of contributing to [International Journal of Clinical Case Reports and Reviews] and for the rigorous review process that enhances the quality of research published in your esteemed journal. I sincerely appreciate the time and effort of your team who have dedicatedly helped me in improvising changes and modifying my manuscript. The insightful comments and constructive feedback provided have been invaluable in refining and strengthening my work".

Dr Shweta Tiwari

I thank the ‘Journal of Clinical Research and Reports’ for accepting this article for publication. This is a rigorously peer reviewed journal which is on all major global scientific data bases. I note the review process was prompt, thorough and professionally critical. It gave us an insight into a number of important scientific/statistical issues. The review prompted us to review the relevant literature again and look at the limitations of the study. The peer reviewers were open, clear in the instructions and the editorial team was very prompt in their communication. This journal certainly publishes quality research articles. I would recommend the journal for any future publications.

Dr Farooq Wandroo

Dear Jessica Magne, with gratitude for the joint work. Fast process of receiving and processing the submitted scientific materials in “Clinical Cardiology and Cardiovascular Interventions”. High level of competence of the editors with clear and correct recommendations and ideas for enriching the article.

Dr Anyuta Ivanova

We found the peer review process quick and positive in its input. The support from the editorial officer has been very agile, always with the intention of improving the article and taking into account our subsequent corrections.

Dr David Vinyes

My article, titled 'No Way Out of the Smartphone Epidemic Without Considering the Insights of Brain Research,' has been republished in the International Journal of Clinical Case Reports and Reviews. The review process was seamless and professional, with the editors being both friendly and supportive. I am deeply grateful for their efforts.

Gertraud Teuchert-Noodt

To Dear Erin Aust – Editorial Coordinator of Journal of General Medicine and Clinical Practice! I declare that I am absolutely satisfied with your work carried out with great competence in following the manuscript during the various stages from its receipt, during the revision process to the final acceptance for publication. Thank Prof. Elvira Farina

Dr Elvira Farina

Dear Jessica, and the super professional team of the ‘Clinical Cardiology and Cardiovascular Interventions’ I am sincerely grateful to the coordinated work of the journal team for the no problem with the submission of my manuscript: “Cardiometabolic Disorders in A Pregnant Woman with Severe Preeclampsia on the Background of Morbid Obesity (Case Report).” The review process by 5 experts was fast, and the comments were professional, which made it more specific and academic, and the process of publication and presentation of the article was excellent. I recommend that my colleagues publish articles in this journal, and I am interested in further scientific cooperation. Sincerely and best wishes, Dr. Oleg Golyanovskiy.

Dr Oleg Golyanovski

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.

Virginia E. Koenig

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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

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

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

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

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