Sains Malaysiana 53(8)(2024): 1953-1968

http://doi.org/10.17576/jsm-2024-5308-18

Synthesis, Molecular Docking and Heme Detoxification of Pyrano[2,3-c]pyrazole-aminoquinoline Hybrids as Potential Antimalarial Agents

(Sintesis, Dok Molekul dan Penyahtoksikan Hem Hibrid Pirano[2,3-c]pirazola-aminokuinolina sebagai Potensi Agen Antimalaria)

LEKKALA RAVINDAR¹, NG YAN HONG², KHAIRUL AZREENA BAKAR², AHMAD FADHLURRAHMAN BIN AHMAD HIDAYAT³, SHEVIN RIZAL FEROZ², SAKI RAHEEM⁴, SITI AISHAH HASBULLAH¹ & NURUL IZZATY HASSAN^1,*

¹Department of Chemical Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor, Malaysia

²Department of Biological Sciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor, Malaysia

³Institute of Biological Sciences, Faculty of Science, Universiti Malaya, 50603 Kuala Lumpur, Malaysia

⁴School of Life Sciences, University of Westminster, 115 New Cavendish Street, W1W 6UW, London, United Kingdom

Received: 11 March 2024/Accepted: 4 July 2024

Abstract

Malaria, an infectious disease that spreads widely and can kill people, is still a problem for global health. This study adds to the list of possible solutions by making a group of new pyrano[2,3-c]pyrazole-aminoquinoline hybrids. Here, five novel hybrids were synthesized by covalently linking the scaffolds of 4-aminoquinoline and pyrano[2,3-c]pyrazoles via an ethyl linker. Molecular docking was used to study each hybrid's and standard chloroquine ability to bind to Plasmodium falciparum lactate dehydrogenase enzyme (PfLDH), an important enzyme in the parasite's glycolytic pathway. The hybrid compounds had a stronger binding affinity than the standard chloroquine. Compound 4c (-7.79 kcal/mol) and 4d (-7.73 kcal/mol) had strong interactions with PfLDH through hydrogen bonds, hydrophobic interactions, and Van der Waals interactions involving Val-26, Ile-54, Ala-98, Phe-100, Lys-118, Ile-119, and Glu-122. Additionally, the study explored the interaction between five hybrids and hemin, a pivotal component in the heme detoxification pathway of malaria parasites. The isothermal titration calorimetry (ITC) showed that the hybrids had different strengths when binding to hemin. This was because their structures were different. Hybrids 4a and 4b showed a strong affinity for hemin with Ka values of (1.43 ± 0.60) × 10⁶ M^-1 and (1.64 ± 0.97) × 10⁶ M^-1, respectively, indicating that they might be able to stop the disruption process. In contrast, hybrids 4c, 4d, and 4e interacted with hemin with markedly lower affinities. This study provides insights into the promising antimalarial properties of pyrano[2,3-c]pyrazole-aminoquinoline hybrids. It details their interactions with PfLDH and hemin and offers potential avenues for developing novel therapeutic strategies against malaria.

Keywords: Isothermal titration calorimetry; Malaria; molecular docking; pyrano[2,3-c]pyrazole-aminoquinoline hybrids

Abstrak

Malaria, sejenis penyakit berjangkit yang merebak secara meluas dan membunuh manusia, masih menjadi masalah kesihatan global. Kajian ini mencari penyelesaian alternatif dengan menghasilkan kumpulan hibrid pirano[2,3-c]pirazola-aminokuinolina baharu. Lima sebatian hibrid baru telah disintesis dengan menghubungkan kerangka 4-aminokuinolina dan pirano[2,3-c]pirazola secara kovalen melalui penghubung etil. Pendokkan molekul digunakan untuk melihat keupayaan hibrid dan piawai klorokuina untuk mengikat enzim Plasmodium falciparum laktat dehidrogenase (PfLDH), enzim penting dalam laluan glikolitik parasit. Sebatian hibrid menunjukkan pertalian pengikatan yang lebih kuat berbanding klorokuina piawai. Sebatian 4c (-7.79 kcal/mol) dan 4d (-7.73 kcal/mol) mempunyai interaksi yang kuat dengan PfLDH melalui ikatan hidrogen, interaksi hidrofobik dan Van der Waals yang melibatkan asid amino Val-26, Ile-54, Ala-98, Phe-100, Lys-118, Ile-119 dan Glu-122. Selain itu, kajian ini meneroka interaksi antara lima hibrid dan hemin, komponen penting dalam laluan detoksifikasi hem parasit malaria. Kalorimetri titrasi isoterma (ITC) menunjukkan perbezaan kekuatan dalam ikatan hibrid terhadap hemin. Hal ini disebabkan struktur hibrid adalah berbeza. Hibrid 4a dan 4b memberikan keafinan yang kuat untuk hemin dengan nilai K_a (1.43 ± 0.60) × 10⁶ M^-1 dan (1.64 ± 0.97) × 10⁶ M^-1, masing-masing, menunjukkan keupayaan perencatan. Sebaliknya, hibrid 4c, 4d dan 4e berinteraksi dengan hemin dengan keafinan yang lebih rendah. Kajian ini menunjukkan potensi antimalaria bagi hibrid pirano[2,3-c]pirazola-aminokuinolina. Interaksi dengan PfLDH dan hemin secara lebih mendalam mampu membuka peluang untuk membangunkan strategi terapeutik baharu terhadap malaria.

Kata kunci: Hibrid pirano[2,3-c]pirazola-aminokuinolina; kalorimetri titrasi isoterma; malaria; pendokkan molekul

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*Corresponding author; email: drizz@ukm.edu.my