Preliminary insight on diarylpentanoids as potential antimalarials: In silico, in vitro pLDH and in vivo zebrafish toxicity assessment
Amirah Hani Ramli,
Puspanjali Swain,
Muhammad Syafiq Akmal Mohd Fahmi,
Faridah Abas,
Sze Wei Leong,
Bimo Ario Tejo,
Khozirah Shaari,
Amatul Hamizah Ali,
Hani Kartini Agustar,
Rusdam Awang,
Yee Ling Ng,
Yee Ling Lau,
Mohammad Aidiel Md Razali,
Siti Nurulhuda Mastuki,
Norazlan Mohmad Misnan,
Siti Munirah Mohd Faudzi,
Cheol-Hee Kim
Affiliations
Amirah Hani Ramli
Natural Medicines and Product Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia
Puspanjali Swain
Department of Biology, Chungnam National University, Daejeon, 34134, South Korea
Muhammad Syafiq Akmal Mohd Fahmi
Natural Medicines and Product Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia
Faridah Abas
Natural Medicines and Product Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia; Department of Food Science, Faculty of Food Science & Technology, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor, Malaysia
Sze Wei Leong
Department of Chemistry, Faculty of Science, University of Malaya, 50603, Kuala Lumpur, Malaysia
Bimo Ario Tejo
Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor, Malaysia
Khozirah Shaari
Natural Medicines and Product Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia
Amatul Hamizah Ali
Department of Earth Sciences and Environment, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi, 43600, Selangor, Malaysia
Hani Kartini Agustar
Department of Earth Sciences and Environment, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi, 43600, Selangor, Malaysia
Rusdam Awang
UPM - MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor, Malaysia
Yee Ling Ng
Department of Parasitology, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
Yee Ling Lau
Department of Parasitology, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
Mohammad Aidiel Md Razali
School of Graduate Studies, Management & Science University, 40100, Shah Alam, Malaysia
Siti Nurulhuda Mastuki
Natural Medicines and Product Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia; Department of Biological Sciences and Biotechnology, Faculty of Science & Technology, Universiti Kebangsaan Malaysia, Bangi, 43600, Selangor, Malaysia
Norazlan Mohmad Misnan
Herbal Medicine Research Centre, Institute for Medical Research, National Institutes of Health, 40170, Shah Alam, Selangor Darul Ehsan, Malaysia
Siti Munirah Mohd Faudzi
Natural Medicines and Product Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia; Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor, Malaysia; Corresponding author. Natural Medicines and Product Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia.
Cheol-Hee Kim
Department of Biology, Chungnam National University, Daejeon, 34134, South Korea; Corresponding author.
Malaria remains a major public health problem worldwide, including in Southeast Asia. Chemotherapeutic agents such as chloroquine (CQ) are effective, but problems with drug resistance and toxicity have necessitated a continuous search for new effective antimalarial agents. Here we report on a virtual screening of ∼300 diarylpentanoids and derivatives, in search of potential Plasmodium falciparum lactate dehydrogenase (PfLDH) inhibitors with acceptable drug-like properties. Several molecules with binding affinities comparable to CQ were chosen for in vitro validation of antimalarial efficacy. Among them, MS33A, MS33C and MS34C are the most promising against CQ-sensitive (3D7) with EC50 values of 1.6, 2.5 and 3.1 μM, respectively. Meanwhile, MS87 (EC50 of 1.85 μM) shown the most active against the CQ-resistant Gombak A strain, and MS33A and MS33C the most effective P. knowlesi inhibitors (EC50 of 3.6 and 5.1 μM, respectively). The in vitro cytotoxicity of selected diarylpentanoids (MS33A, MS33C, MS34C and MS87) was tested on Vero mammalian cells to evaluate parasite selectivity (SI), showing moderate to low cytotoxicity (CC50 > 82 μM). In addition, MS87 exhibited a high SI and the lowest resistance index (RI), suggesting that MS87 may exert effective parasite inhibition with low resistance potential in the CQ-resistant P. falciparum strain. Furthermore, the in vivo toxicity of the molecules on early embryonic development, the cardiovascular system, heart rate, motor activity and apoptosis were assessed in a zebrafish animal model. The overall results indicate the preliminary potential of diarylpentanoids, which need further investigation for their development as new antimalarial agents.
