EXPLORATION OF ANALGESIC POTENTIALS OF BENZOFURAN PYRAZOLE HETEROCYCLE AND AZOSALICYCLIC ACID THROUGH MOLECULAR DOCKING, PHARMACOKINETICS AND DFT STUDIES

                       

Title page………………………………………………………………………………………I

Declaration………………………………………………………………….………………..II

Certification………………………………………………………………….……………….III

Dedication……………………………………………………………………………………IV

Acknowledgements……………………………………………………………………....…...V

Table of contents………………………………………………………………………….…..VI

List of tables…………………………………………………………………………………...X

Abstract………………………………………………………………………………………..XI

1.0 Introduction…………………………………………………...……………..1

1.4 Aim and objectives…………………………………………………………………………..3

2.0 Literature Review……………………………………………………………………………5

2.1 Biochemical and physiological Basis of pain………………………………………………..5

3.1Materials ……………………………………………………………………………………..16

3.2 Geometry optimization /DFT method………………………………………………………..16

3.3 Molecular Docking method………………………………………………………………….17

4.0 Result and discussion…………………………………………………………………………23

4.11 Molecular electrostatic potential…………………………………………………………….42

5.1 Conclusion…………………………………………………………………………..45

5.2 Recommendations…………………………………………………………………..46

      References…………………………………………………………………………..47

Table 3.1 2D structures of compounds…………………………………………………………. 19

Table 4.1 Docking results of ligands in benzofuran pyrazole heterocycle……………………..  23

Table 4.2 Molecular interaction of five best docked ligands in benzofuran pyrazole heterocycle……………………………………………………………………………………… 24

Table 4.3 predicted Drug-likeness properties of ligands in benzofuran pyrazole heterocycle……………………………………………………………………………………… 28

Table 4.4 evaluation of ADMET properties of ligands in benzofuran pyrazole heterocycle…….29

Table 4.5 DFT evaluation results of benzofuran pyrazole heterocycle………………………… .33

Table 4.6 docking results of ligands in azosalicyclic acid……………………………………….34

Table 4.7 molecular interaction of ligands in azosalicyclic acid……………………………………………………………………………………………… 35

Table 4.8 predicted Drug-likeness properties of ligands in azosalicyclic acid…………………. 37

Table 4.9 evaluation of ADMET properties of ligands in azosalicyclic acid……………………38

Table 4.10 DFT evaluation result in azosalicyclic acid………………………………………… 41

                               

                                       

Figure 3.1 Flowchart representation of research methodology…………………….…………. 18

Figure 4.1 3D and 2D Representation for interaction of complex 14………………………….25

Figure 4.2 3D and 2D Representation for interaction of complex 16, 17 and 18…………...…26

Figure 4.3 3D and 2D Representation for interaction of complex 20 and SD……………….... 27

Figure4.4Optimizedgeometricstructures of studied ligands 14, 16, 17, 18 and 20………….... 31

Figure 4.5 Frontier molecular orbitals of ligand 14, 16, 17, 18 and 20………………………. 32

Figure 4.6 Frontier molecular orbitals of ligand 20 and SD………………………………….. 33

Figure 4.7 3D and 2D Representation for interaction of complex 1, 2 and 5………..……….. 36

Figure 4.8 3D and 2D Representation for interaction of complex 3, 4 and SD………………. 37

Figure 4.9 Optimized geometric structures of ligand 1, 2, 3, 4 and 5……………………….... 39

 Figure 4.10 Frontier molecular orbitals of ligand 1, 2, 3, 4 and 5………………………….... 40

Figure 4.11 molecular electrostatic potentials of 14, 16, 17, 18 and 20……………………..... 43

Figure 4.12 molecular electrostatic potentials of 1, 2, 3, 4 and 5…………………………..… 44

Pain is defined as multidimensional, subjective and unpleasant experience that is allied to tissue damage comprising sensory experiences that include; time, intensity, space, emotion, cognition and motivation (Kremer et al., 2021). Pain contains both sensory and psychological mechanisms. However, pain is beyond sensation, it comprises of perception and subjective interpretation of the discomfort(Kremer et al., 2021). Major mediators of pain include; Bradykinin, histamine, serotonin and prostaglandins. Pain in its real sense lack a way to define it, but in general term, occurs whenever the body tissues are damaged (Arome et al., 2016). Sensation of pain is a sign that something in the body is wrong. Pain plays an important role in drawing attention to tissue injury from harmful stimuli and reflexes are elicited to protect the injured part of the body (Arome et al., 2016). Damage caused by mechanical, thermal, chemical and electrical stimuli through peripheral receptors triggers pain sensation to nociceptors in an organism (Gianò et al., 2023). Perception of pain is a normal physiological response that is mediated by nervous system and is used for diagnosing various diseases such as diabetes, arthritis and cancer that are normally associated with chronic pain (Clauw et al., 2019).

Pain, are beneficial to the immune system. However, they cause a lot of suffering and discomfort to the victims lowering the quality of life and therefore need to be managed. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to manage pain (Kołecka  et al., 2022). Opioid analgesics are choice drugs for severe or chronic malignant pain (Bertin et al., 2021). Their mechanism of action involves inhibition of cyclooxygenase (COX) enzyme which results in disruption of prostaglandins synthesis (Johnson et al., 2020). However, non-steroidal anti-inflammatory drugs and opioid analgesics that are normally used to treat pain manifest a great number of adverse effects (Huang et al., 2020). Despite numerous progress in medical science and in the production of new synthetic conventional drugs for management of pain, there is still need for development of more cost-effective and improved remedies with lesser side effects. Recent studies by world health organization (WHO) indicate that these compounds/drugs used in the management of pain, manifest a lot of side effects after long term use that include gastric irritation, ulceration, prolonged bleeding, renal failure, interstitial corrosion, and pruritis (Huang et al., 2020). Reduction in ligament formation, tendon, cartilage healing and delay in muscle regeneration in many studies has been associated with NSAIDs (Roffino et al., 2021). Conventional drugs used to manage pain, only provide asymptomatic relief and the greatest disadvantage lies in their toxicity to the liver, kidney and reappearance of symptoms after discontinuation (Carrarini et al., 2019). In this regard, herbal medicines have been employed in complementary and alternative medicine (CAM) for treatment of pain, as well as diseases related to these conditions. In general, natural products and in particular, medicinal plants, are believed to be an important source of novel chemical substances with potential therapeutic capabilities. Considering that most of anti-inflammatory, analgesic, anti-malarial and antipyretic synthetic drugs such as aspirin, morphine chloroquine and artemisinin were derived from plant products, the search for plant species with anti-inflammatory, antipyretic and analgesic properties should be viewed as a fruitful strategy in search of new drugs (Tatiya et al., 2017).  

Recently, there has been a remarkable development in medical science. Pain cause suffering and discomfort among the victims (Levkovich, et al., 2020). Recent studies by WHO indicates that the NSAIDs used in management of these condition manifest a lot of side effects (Huang et al., 2020). However, treatment and management of many serious indicators of ill health is still a problematic and complex (Rodgers et al., 2018). Therefore, a challenge to the research sector to find alternative approaches of managing pain as well as reduce the dangers associated with experimental screening efforts set. Computational studies offers a method for identifying and optimizing potentials compounds with increased activity for curing of pains. Hence, there is need for chemists to suggest new potentials drugs which are more effective within a short period of time.

Therefore, there should be provision of alternative drugs that has more cost-effectiveness and improved remedies with lesser side effects to web lab drug discovery and to of Benefit to researchers in field of pharmaceutical and academia chemistry

The aim of the research is to explore the analgesic potentials of benzofuran pyrazole heterocycle and azosalicyclic acid through molecular docking, pharmacokinetics and DFT studies.

Through the following objectives to;