Quantum Modelling for Anti-Human African Trypanosomiasis Activity of Substituted 2 - Phenylimidazopyridines; QSAR Approach

Hassan S., Oladunni N., Uwaiya E., Magaji I. Y., Amos A. K., Omotola M. B.

Abstract


Human African Trypanosomiasis (HAT), commonly known as sleeping sickness, remains a critical public health concern in sub-Saharan Africa. It is caused by the protozoan parasites Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, transmitted by the tsetse fly (Glossina). HAT is a disease driven by an underlying lack of effective treatment options, with current therapies suffering from high toxicity, poor bioavailability, and resistance issues. QSAR analysis was performed on the anti-trypanosomal activity of substituted 2-phenylimidazopyridines. A large number of molecular descriptors were calculated using semi-empirical methods, and a genetic function algorithm (GFA) approach was used to develop the best predictive model with high statistical significance (R² = 0.89228, Radj = 0.87074, Q² = 0.81896, cRp = 0.15428, R²pred = 0.72734, r²₀ = 0.82387, r²₀ = 0.81947, (r²₀ - r²₀) / r² = 0.01695, r²₀ - r²₀ = 0.0044, k = 0.71507, r² - r²₀ + r² = 0.02219). The study reveals that the molecular descriptors (AMR, AATSC7c, and E3u) significantly contribute to the enhanced anti-trypanosomal activity of these compounds, providing valuable insights for future drug design.


Full Text:

PDF

References


Baker, N., de Koning, H. P., Mäser, P., & Horn, D. (2013). Drug resistance in African trypanosomiasis: The melarsoprol and pentamidine story. Trends in Parasitology, 29(3), 110-118.

Barrett, M. P., & Croft, S. L. (2012). Management of trypanosomiasis and leishmaniasis. British Medical Bulletin, 104(1), 175-196.

Barrett, M. P., Vincent, I. M., Burchmore, R. J., Kazibwe, A. J., & Matovu, E. (2011). Drug resistance in human African trypanosomiasis. Future Microbiology, 6(9), 1037-1047.

Walters, W. P., & Barzilay, R. (2020). Applications of deep learning in molecule generation and molecular property prediction. Accounts of chemical research, 54(2), 263-270.

Büscher, P., Cecchi, G., Jamonneau, V., & Priotto, G. (2017). Human African trypanosomiasis. The Lancet, 390(10110), 2397-2409.

Büscher, P., Mertens, P., Leclipteux, T., Pyana, P. P., & Boelaert, M. (2014). Sensitivity and specificity of HAT Sero-K-SeT, a rapid diagnostic test for sleeping sickness. PLOS Neglected Tropical Diseases, 8(10), e3183.

Chappuis, F., Loutan, L., Simarro, P., Lejon, V., & Büscher, P. (2005). Options for field diagnosis of human African trypanosomiasis. Clinical Microbiology Reviews, 18(1), 133-146.

Chtita, S., El-Abd, A. E., & El-Sayed, N. N. (2019). Predictive modeling and structure-activity relationship of anti-HAT activity using QSAR techniques. Journal of Molecular Modeling, 25(6), 134-145.

Consonni, V., & Todeschini, R. (2009). Molecular Descriptors. In Handbook of Chemoinformatics Algorithms (pp. 29–122). CRC Press.

Elrufaie, H. A., Mohamed, L. M., Hamd, A. Y., Bala, N. A., Elbadawi, F. A., Ghaboosh, H., & Alzain, A. A. (2023). Discovery of novel natural products as rhodesain inhibitors for human African trypanosomiasis using in silico techniques. Journal of Biomolecular Structure and Dynamics, 41(12), 5672-5684.

Eriksson, L., Jaworska, J., Worth, A. P., Cronin, M. T. D., McDowell, R. M., & Gramatica, P. (2003). Methods for reliability and uncertainty assessment and for applicability evaluations of classification- and regression-based QSARs. Environmental Health Perspectives, 111(10), 1361–1375.

Fairlamb, A. H. (2003). Chemotherapy of human African trypanosomiasis: Current and future prospects. Trends in Parasitology, 19(11), 488-494.

Franco, J. R., Simarro, P. P., Diarra, A., & Jannin, J. G. (2014). Epidemiology of human African trypanosomiasis. Clinical Epidemiology, 6, 257-275.

Galvez, J., Garcia-Domenech, R., de Julian-Ortiz, J. V., & Pogliani, L. (1994). Topological charge indices for predicting the biological activity of drugs. Journal of Chemical Information and Computer Sciences, 34(3), 520–525.

Ghose, A. K., & Crippen, G. M. (1986). Atomic physicochemical parameters for three-dimensional QSAR. Journal of Computational Chemistry, 7(4), 565–577.

Henao-Martínez, A. F. (2023). Human African trypanosomiasis (Sleeping Sickness)—Epidemiology and control. Current Tropical Medicine Reports, 10(2), 81-89.

Idrissi Taourati, A. (2015). QSAR study of anti-Human African Trypanosomiasis activity for 2-phenylimidazopyridines derivatives using DFT and Lipinski's descriptors. Journal of Molecular Modeling, 21(6), 134.

Kennedy, P. G. (2013). Clinical features, diagnosis, and treatment of human African trypanosomiasis (sleeping sickness). The Lancet Neurology, 12(2), 186-194.

Kennedy, P. G. E. (2004). Human African trypanosomiasis of the CNS: Current issues and challenges. The Journal of Clinical Investigation, 113(4), 496-504.

Requirements of imidazopyridine analogues as anti-infective agents against trypanosomiases. Journal of Computational Biophysics and Chemistry, 21(01), 83-114.

Masand, V. H., El-Sayed, N. N., Bambole, M. U., Patil, V. R., & Thakur, S. D. (2019). Multiple quantitative structure-activity relationships (QSARs) analysis for orally active trypanocidal N-myristoyltransferase inhibitors. Journal of Molecular Structure, 1175, 481-487.

Masand, V. H., El-Sayed, N. N., Mahajan, D. T., Mercader, A. G., Alafeefy, A. M., & Shibi, I. G. (2017). QSAR modeling for anti-human African trypanosomiasis activity of substituted 2-Phenylimidazopyridines. Journal of Molecular Structure, 1130, 711-718.

Nnadi, C. O., Althaus, J. B., Nwodo, N. J., & Schmidt, T. J. (2018). A 3D-QSAR study on the antitrypanosomal and cytotoxic activities of steroid alkaloids by comparative molecular field analysis. Molecules, 23(5), 1113.

Nnadi, E. O., Olaifa, A. K., & Fadaka, A. O. (2018). Advances in the search for new anti-trypanosomal agents: A comprehensive review. Drug Development Research, 79(4), 450-465.

Papagni, R., Novara, R., Minardi, M. L., et al. (2023). Human African trypanosomiasis (sleeping sickness): Current knowledge and future challenges. Frontiers in Tropical Diseases, 4, 1087003.

Pépin, J., & Méda, H. A. (2001). The epidemiology and control of human African trypanosomiasis. Advances in Parasitology, 49, 71-132.

, P. D., Østergaard, S., Kristensen, T. N., Sørensen, P., Loeschcke, V., Mackay, T. F., & Sarup, P. (2018). Functional validation of candidate genes detected by genomic feature models. G3: Genes, Genomes, Genetics, 8(5), 1659-1668.

Simarro, P. P., Jannin, J., & Cattand, P. (2010). Eliminating human African trypanosomiasis: Where do we stand and what comes next? PLoS Medicine, 7(8), e1000325.

Steverding, D. (2008). The history of African trypanosomiasis. Parasites & Vectors, 1(1), 3.

The Sun. (2024). Deadly 'sleeping sickness' that causes fever to psychosis 'risking worldwide spread'. The Sun.

Todeschini, R., & Consonni, V. (2000). Handbook of Molecular Descriptors. Wiley-VCH.

Tin, N., Chauhan, M., Agwamba, K., Sun, Y., Parsons, A., Payne, P., & Osan, R. (2024). Evaluating Molecular Complexity with Open-Source Machine Learning Approaches to Predict Process Mass Intensity. ACS omega, 9(26), 28476-28484.

World Health Organization. (2023). Guidelines for the treatment of human African trypanosomiasis.

Hossain, M. S., & Hussain, M. H. (2025). Multi‐Target Drug Design in Alzheimer's Disease Treatment: Emerging Technologies, Advantages, Challenges, and Limitations. Pharmacology Research & Perspectives, 13(4), e70131.

Kiriiri, G. K., Njogu, P. M., & Mwangi, A. N. (2020). Exploring different approaches to improve the success of drug discovery and development projects: a review. Future Journal of Pharmaceutical Sciences, 6(1), 27

Buckner, F. S., Buchynskyy, A., Nagendar, P., Patrick, D. A., Gillespie, J. R., Herbst, Z. & Gelb, M. H. (2020). Phenotypic drug discovery for human african trypanosomiasis: a powerful approach. Tropical Medicine and Infectious Disease, 5(1), 23

Zhang, Y., Niu, J., & Na, S. (2019). A novel nonlinear function fitting model based on FOA and GRNN. Mathematical Problems in Engineering, 2019(1), 2697317.

Jabeen, F. (2024). Application of Machine Learning and Deep Learning Approaches Cheminformatic for Drug Discovery (Doctoral dissertation, Carleton University).

Maghsoudi, S., Hosseini, S. A., & Ravandi, S. (2022). Liposome Carriers: Synthetic Methods and Their Applications in Drug Delivery. Journal of Chemical Reviews, 4(4).

Manzari, M. T., Shamay, Y., Kiguchi, H., Rosen, N., Scaltriti, M., & Heller, D. A. (2021). Targeted drug delivery strategies for precision medicines. Nature Reviews Materials, 6(4), 351-370.


Refbacks

  • There are currently no refbacks.