Molecular Characterization and Pharmacokinetic Differentiation of Boswellia serrata Derivatives and Zileuton

Hrutuja Wagh*, Vishal Girbane, Riya Sakore, Prashanti Matte

Department of Pharmaceutical Chemistry,

Tilak Maharashtra Vidyapeeth’s Lokmanya Tilak Institute of Pharmaceutical Sciences, Pune, India 411037.

*Corresponding Author E-mail: hrutuja3196@gmail.com

ABSTRACT:

This Research assesses and contrasts the antiinflammatory efffect of natural derivatives from Boswellia serrata tree with the synthetic medication Zileuton, concentrating on their ADMET Absorption, Distribution, Metabolism, Excretion, and Toxicology profiles. Boswellia serrata, acclaimed for its medicinal potential, contains substances such as Acetyl-11-Keto-Boswellic Acid (AKBA), β-Boswellic Acid (BBA) , Acetyl-β-Boswellic Acid (ABBA), and 11-Keto-β-Boswellic Acid (KBBA). Specifically, AKBA displays a high docking affinity of -6.581Kcal/mol, underscoring its effectiveness in inhibiting 5-lipoxygenase, a crucial enzyme involved in inflammation. Although its bioavailability is lower compared to other Boswellic acids, it demonstrates notable drug-like characteristics and hydrophobic properties. In comparism, KBBA achieves the highest docking value of -6.810Kcal/mol, reflecting superior binding potential and effective anti-inflammatory activity. Zileuton, while effective in inhibiting leukotriene synthesis and showing good gastrointestinal absorption, has the highest docking affinity of -7.510Kcal/mol. Nonetheless, it is linked with higher toxicity risks, including potential liver damage and carcinogenicity. In summary, AKBA is highlighted as the most potent natural anti-inflammatory compound with favorable ADMET properties, whereas Zileuton, despite its therapeutic advantages, presents significant safety concerns.

KEYWORDS:5-Lipoxygenase Inhibition, ADME, Anti-Inflammatory Agents, Drug-Like Properties, Toxicity.

INTRODUCTION: 

This research assesses and contrasts the natural anti-inflammatory effects of Boswellia serrata with the synthetic drug Zileuton. An anti-inflammatory agent reduces inflammation—manifested as redness, swelling, and pain—by inhibiting the substances responsible for these symptoms. Such agents are widely utilized for managing various conditions¹. The concept of inflammation, originating from early medical traditions, was once associated with symptoms such as inflammmation and and other  impaired function.

Conditions that are marked by significant inflammation typically end with the suffix -itis, and the immune system’s cellular and humoral responses play a critical role in managing this inflammatory process². Serving as an additional defense mechanism against pathogens, inflammation is crucial in the development of various illnesses. The lipoxygenase pathway, which is predominantly active in the lungs, white blood cells, and platelets, is integral to this process. Among these, LTB4 serves as a powerful chemotactic factor, while LTC4 and LTD4 are involved in forming the substance causing anaphylaxis. The transfer protein FLAP (five-lipoxygenase activating protein) is essential for transporting arachidonic acid to 5-lipoxygenase, facilitating the synthesis of inflammatory leukotrienes³. Leukotrienes are pivotal in driving inflammation. This pathway produces key compounds known as leukotrienes, synthesized by the enzyme 5-lipoxygenase. While inflammation is essential for healing and combating infections, it can also lead to long-term diseases. In contemporary terms, it is understood as a sophisticated response to tissue damage that may arise from harmful substances, environmental influences, injuries, excessive use, or infections⁴.

Boswellia serrata:

Boswellia serrata is a medium to tree belonging to the Burseraceae family, found in arid zone across India and other parts of globe. The tree contains important compounds such as BBA and AKBA, with the latter being particularly noted for its ability to inhibit 5-lipoxygenase, an enzyme associated with inflammation^5,6,7. In traditional medicinal practices, it is used to address various ailments such as gastrointestinal issues, fungal infections, skin conditions, fevers, blood disorders, Heart problems, mouth sores, throat inflammation, and respiratory issues^8,9,10. This tree family consists of about six hundred species, primarily located in tropical areas. The resin is harvested by making incisions in the trunk to collect the fluid, which solidifies into tear-shaped pieces after being stored in bamboo baskets. The Boswellia genus includes roughly twenty-five species, predominantly found in dry region.The resin provides a range of benefits for, in nature^11,12.

Figure No. 1 Bowellia serrata Tree and it’s Resin

Table 1. Chemical Structure of Boswellia serrata Derivatives^13-15.

ABBA	BBA
AKBA	KBBA

Zileuton:

Zileuton is a medication used for asthma management with a distinct chemical and pharmacological profile. It works by inhibiting 5-lipoxygenase, an enzyme crucial for producing leukotrienes, which are inflammatory mediators involved in asthma. These leukotrienes, including leukotriene C4, D4, E4 (slow-reacting substances of anaphylaxis), and leukotriene B4, play key roles in inflammation and airway constriction. They are derived from leukotriene A4, an intermediate in arachidonic acid metabolism, and can be detected in biological fluids of asthma patients. Clinical studies show that zileuton can reduce bronchoconstriction when administered before cold air exposure in asthma patients^17,18.

Figure 2. Structure of Zileuton¹⁷.

Mechanism of action (MOA):

Leukotrienes bioactive are the agents that have various effects, such as promoting migration of eosinophils and neutrophils. These actions contribute to Swelling and irritaton seen in asthma. Zileuton manages these symptoms by inhibiting 5-lipoxygenase, an essential component for leukotriene formation  from arachidonic acid. This inhibition prevents the production of key leukotrienes. zileuton are active in blocking 5-lipoxygenase, thereby reducing airway inflammation, and bronchial smooth muscle contraction and improving asthma control¹⁷.

Molecular Docking:

It is a vital method in drug development drug design. It focuses on predicting how a protein molecules binds to ligand molecules with a known 3D structure. The technique explores complex multidimensional spaces and uses scoring functions to rank binding interactions effectively.

Table 2. Molecular Docking of AKBA (A) and KBBA (B).

A

B

Table 3.  Molecular Docking of Synthetic Drug Zileuton

Zileuton (Synthetic Drug)

MATERIAL AND METHOD:

ADMET Testing:

ADMET assesses how a drug is absorbed in the body and distributed across the differents body parts and  metabolized by different enzymes and excreted by the body. These evaluations are essential for determining a drug's safety and efficacy and are necessary for regulatory approvals. Database screening supports the selection of appropriate compounds based on these characteristics.

1. Swiss adme:

Swissadme is an accessible online software that assesses the pharmacokinetics of the drug molecules and medicinal chemistry of compounds. It offers a straightforward approach for analyzing adme attributes. By evaluating different pharmacokinetic parameters and drug-like properties, swissadme enables researchers to rapidly ascertain whether a molecule possesses the critical features needed for drug development¹⁹.

2. Admet lab 3.0:

Admet lab 3.0 provides comprehensive adme calculations, while swissadme predicts drug characteristics by analyzing 21 physicochemical properties, 19 medicinal chemistry features, and various adme and toxicity endpoints. This tool is crucial for evaluating and optimizing drug candidates²⁰.

3. Pubchem: 

Pubchem Provided The 2-D Structures And Smiles Strings Of Four Boswellia Serrata Ligands, Which Were Analyzed Using Swissadme And Admet Lab 3.0 Software For Adme Properties^21,22,23.

Lipinski Rule:

The Lipinski Rule of 5 is a guideline for evaluating the drug-likeness of molecules, predicting their potential success as drugs. The rule is based on the following criteria: Molecules meeting two or more of these criteria are generally more likely to be effective drugs.

1. Molecular Weight : Less than 500 Dalton.

2. LogP (partition coefficient) value under 5.

3. (H- Bond) Donors: should be less than 5.

4. (H- Bond) Acceptors:should be less than 10.

5. Molar Refractivity: Between 40 and 130.

RESULT:

In this article, we have compared a natural drug, Boswellia Serrata, with a synthetic drug, Zileuton. Below are the ADMET predictions for both compounds

Molecular Docking:

Table  4.  Molecular Binding Affinity of Natural and Synthetic drug.

Drug Molecules	Calculated Affinity (Kcal/mol)			Higest Affinity (Kcal/mol)
	Model 1	Model 2	Model 3
Acetyl-11-Keto Boswellic Acid	-6.581	-6.081	-5.554	-6.581
Beta Boswellic Acid	-5.820	-3.171	-	-5.820
Acetyl Beta Boswellic Acid	-4.476	-2.564	-	-4.476
11-Keto-Beta Boswellic Acid	-6.810	-6.581	-5.252	-6.810
Zileuton (Synthetic Drug)	-7.510	-7.148	-6.864	-7.510

Medicinal Chemistry:

Table 5. Data Analysis by ADMETLAB 3.0.

Parameter	AKBA	BBA	ABBA	KBBA	Zileuton (Synthetic Drug)
Lipinskies Rule	+	+	+	+	+
QED (Drug Likeness)	0.41	0.414	0.313	0.474	0.622
Pfizeres  Rule	+	-	-	-	+
GSK Rule	-	-	-	-	+
GoldenTriangle	-	+	+	+	+

(Abbrevation : Accepted (+), Rejected (-)

Absorption:

A. Caco-2Permeability: Caco-2 permeability ranks compounds by their ability to pass through the intestinal cell layer. The order from highest to lowest permeability is: KBBA, ABBA, BBA, AKBA, and Zileuton.

B. G.I.Absorption: Zileuton and KBBA have higher G.I. absorption compared to other compounds, while AKBA, BBA, and ABBA have lower absorption.

Distribution:

Table 6. Data Analyses by SWISS ADME Software.

Parameter	AKBA	BBA	ABBA	KBBA	Zileuton (Synthetic drug)
Number of h-bond acceptor	5	3	4	4	4
Number of’H-bond donars	1	2	1	2	3
LOGp	4.07	3.85	3.98	3.48	1.85
LOGS	-7.37	-7.81	-7.96	-7.23	-2.54
MLOGP	5.14	5.82	6.06	4.87	1.77
Bioavailability	0.56	0.85	0.85	0.85	0.55
Skin Permeation	-4.30	-3.22	-3.46	-4.06	-6.60

Table 7. Data Analysis by ADMETLAB 3.0.

Parameter	AKBA	BBA	ABBA	KBBA	Zileuton (synthetic drug)
LOGp	3.592	4.27	5.036	3.333	1.978
LOGS	-4.893	-5.183	-4.852	-4.205	-3.337
PPB <90%.	96.70	88.30	97.00	97.40	93.30
VDss	0.283	0.53	0.502	0.263	1.779

Metabolism

Table 8.  Data Analysis by ADMETLAB 3.0.

Parameter	AKBA	BBA	ABBA	KBBA	Zileuton (synthetic drug )
CYP1A2 inhibitor	-	-	-	-	-
CYP2C19 inhibitor	-	-	-	-	-
CYP2C92 inhibitor	-	+	-	+	-
CYP2D6 inhibitor	-	-	-	-	-
CYP3A4 inhibitor	-	-	-	-	-

(Abbrevation : NO (-), YES (+) )

Toxicity:

Table 10. Toxicity study By ADMET LAB 3.0.

Parameters	AKBA	BBA	ABBA	KBBA	Zileuton (Sunthetic drug)
Liver Injury	0.28	0.19	0.735	0.755	0.847
AMES Toxicity	0.075	0.047	0.216	0.253	0.879
Rat Oral Acute Toxicity	0.135	0.083	0.287	0.292	0.198
Carcinogenicity	0.404	0.464	0.604	0.983	0.936
Human Hepatotoxicity	0.538	0.548	0.494	0.874	0.878
Drug-induced Nephrotoxicity	0.144	0.075	0.739	0.951	0.677
Drug-induced Neurotoxicity	0.2	0.131	0.072	0.039	0.523
Hematotoxicity	0.538	0.548	0.494	0.874	0.878
Genotoxicity	0.012	0.001	0.628	0.868	1
Eye Irritation	0.084	0.057	0.424	0.917	0.14
Skin Sensitization	0.089	0.022	0.68	0.979	0.46
RPMI-8226 Immunitoxicity	0.031	0.022	0.034	0.047	0.095

Excretion:

Table 9. Clearance and t ½ Analysis by ADMET LAB 3.0.

Parameters	AKBA	BBA	ABBA	KBBA	Zileuton (Syntheic drug )
Clearance	1.75	3.778	2.803	5.581	1.768
T1/2	1.044	1.376	0.904	0.904	2.873

Figure 2.  Target Prediction of Swiss Target Prediction Software.

Figure 3. Radar view of AKBA (Left) and KBBA (Right)

CONCLUSION:

Among the natural compounds studied—AKBA, BBA, ABBA, and KBBA—each demonstrates distinct ADMET profiles and compliance with Lipinski's Rule of Five, indicating favorable oral bioavailability. AKBA stands out for its strong 5-lipoxygenase inhibition, with a docking affinity of -6.581kcal/mol. Despite its lower bioavailability (0.56), AKBA exhibits the highest number of hydrogen bond acceptors and significant hydrophobicity (LogP 4.07), which supports effective distribution within the body. KBBA, on the other hand, shows exceptional Caco-2 permeability and the highest docking affinity among the natural compounds (-6.810 kcal/mol), reflecting superior intestinal absorption and strong binding efficiency. Additionally, KBBA's high QED score (0.474) highlights its excellent drug-like properties, although its high clearance and short half-life suggest rapid elimination. In comparison, Zileuton, a synthetic drug, exhibits the highest docking affinity (-7.510kcal/mol) and superior gastrointestinal absorption. However, its use is significantly limited by safety concerns, including drug-induced liver injury, AMES toxicity, carcinogenicity, and hepatotoxicity. While Zileuton’s drug-like properties are notable, its toxicity profile makes it less favorable than the natural Boswellic acids.

Overall, AKBA emerges as the most potent natural compound, combining strong 5-lipoxygenase inhibition with a favorable ADMET profile. KBBA also demonstrates high efficacy and excellent drug-like properties, making both compounds safer and more effective alternatives to Zileuton for therapeutic applications. These findings highlight the potential of natural Boswellic acids as safer, efficacious candidates for further drug development.

ACKNOWLEDGMENT:

The authors wish to express their gratitude to all the co-authors for their valuable guidance and support.

REFERENCES:

1. Stone WL, Basit H, Zubair M, et al. Pathology, Inflammation. [Updated 2024 Aug 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK534820

2. NIH National Cancer Institute. Available: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/anti-inflammatory-agent

3. Singh D, Boyce M, Norris V, Kent SE, Bentley JH. Inhibition of the early asthmatic response to inhaled allergen by the 5-lipoxygenase activating protein inhibitor GSK2190915: a dose-response study. Int J Gen Med. 2013; Dec 9; 6: 897-903. doi: 10.2147/IJGM.S51364.

4. K. Tripathi, Essentials of medical Pharmacology, 8th ed., New Delhi: Jaypee Brothers Medical Publishers (P) Ltd, 2019, pp. 197-198

5. Siddiqui MZ. Boswellia serrata, a potential antiinflammatory agent: an overview. Indian J Pharm Sci. 2011; May; 73(3): 255-61. doi: 10.4103/0250-474X.93507

6. Chaudhary, Gitika and Kumari, Isha. Boswellia serrata ROXB. EX COLEBR. (Salai): An Ayurvedic Herb with Anti-inflammatory Potential. International Journal of Pharmaceutical Sciences Review and Research. 2021; 69. 10.47583/ijpsrr.2021.v69i01.024.

7. Karen Pilkington, Geoffrey John Pilkington, Boswellia: Systematically scoping the in vitro, in vivo and clinical research, European Journal of Integrative Medicine, Volume 56,2022,102197, https://doi.org/10.1016/j.eujim.2022.102197

8. Yu, G., Xiang, W., Zhang, T. et al. Effectiveness of Boswellia and Boswellia extract for osteoarthritis patients: a systematic review and meta-analysis. BMC Complement Med Ther. 2020; 20: 225. https://doi.org/10.1186/s12906-020-02985-6

9. Available at https://www.nbihealth.com/boswellia-serrata-new-uses-for-an-old-plant/

10. Soni, Anuj and Bohra, Naveen. (2021). International Journal of Advanced Research in Biological Sciences Boswellia serrata -Propogation and uses -A Review. 10.22192/ijarbs.2021.08.05.005

11. Basch, Ethan and Boon, Heather and Davies-Heerema, Theresa and Foppo, Ivo and Hashmi, Sadaf and Hasskarl, Jens and Sollars, David and Ulbricht, Catherine. Boswellia: An evidence-based systematic review by the Natural Standard Research Collaboration. Journal of Herbal Pharmacotherapy. 2004; 4: 63-83. 10.1080/J157v04n03

12. Martins, Olabode and Olabintan, Olabode and Wahab, Yusuf and Ahmed, Nurain. Exploring the anticancer potential of Boswellia serrata: A comprehensive review. GSC Biological and Pharmaceutical Sciences. 2024; 26: 349-362. 10.30574/gscbps.2024.26.1.0027

13. National Center for Biotechnology Information. PubChem Compound Summary for CID 11168203, 3-acetyl-11-keto-beta-boswellic acid. [online]. Available: https://pubchem.ncbi.nlm.nih.gov/compound/3-acetyl-11-keto-beta-boswellic-acid.

14. National Center for Biotechnology Information. PubChem Compound Summary for CID 168928, Beta-Boswellic Acid" PubChem, [Online]. Available: https://pubchem.ncbi.nlm.nih.gov/compound/Beta-Boswellic-Acid

15. National Center for Biotechnology Information. PubChem Compound Summary for CID 134159359, 3-Acetyl-beta-boswellic acid, HPLC Grade" PubChem, [Online]. Available: https://pubchem.ncbi.nlm.nih.gov/compound/134159359

16. National Center for Biotechnology Information. PubChem Compound Summary for CID 9847548, 11-KETO-beta-BOSWELLIC ACID" PubChem, [Online]. Available: https://pubchem.ncbi.nlm.nih.gov/compound/9847548

17. National Center for Biotechnology Information. PubChem Compound Summary for CID 60490, Zileuton PubChem,," [Online]. Available: https://pubchem.ncbi.nlm.nih.gov/compound/60490

18. Koen YM, Sarma D, Williams TD, Galeva NA, Obach RS, Hanzlik RP. Identification of protein targets of reactive metabolites of tienilic acid in human hepatocytes. Chem Res Toxicol. 2012 May 21;25(5):1145-54. doi: 10.1021/tx300103j. Epub 2012 Apr 10. PMID: 22462724; PMCID: PMC3358484

19. Daina, A., Michielin, O. and Zoete, V. Swiss ADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 7, 42717 (2017). https://doi.org/10.1038/srep42717

20. Available at, https://admetlab3.scbdd.com/

21. Available at, Available: https://pubchem.ncbi.nlm.nih.gov/.

22. Girbane, Vishal and Kedari, Rasika and Munde, Rushikesh. In silico docking and ADMET evaluation of bioactive compounds from Phyllanthus niruri and captopril as angiotensin-converting enzyme (ACE) inhibitors for hypertension management. International Journal of Science and Research Archive. 2025; 14: 423-433. 10.30574/ijsra.2025.14.1.0038

23. Wagh, Hrutuja and Bhosale, Avinash and Girbane, Vishal and Bhosale, Shravanee and Bhise, Manish and Deshpande, Mahesh and Chandra, Piyush and Ranjan, Rakesh. Popping balls papaya extract: Preparation of pediatric dosages in therapeutic formulations for therapeutic usage in dengue and malaria. International Journal of Experimental Research and Review. 2023; 32: 188-194. 10.52756/ijerr.2023.v32.016

Received on 12.09.2024      Revised on 15.01.2025

Accepted on 17.03.2025 Published on 05.09.2025

Available online from September 08, 2025

Research J. Pharmacy and Technology. 2025;18(9):4269-4274.

DOI: 10.52711/0974-360X.2025.00613

© RJPT All right reserved

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.