Rational Design and Lead Optimisation of Potent Antimalarial Quinazolinediones and Their Cytotoxicity against MCF-7
Abstract
:1. Introduction
2. Results and Discussion
2.1. SwissADME In Silico Prediction
2.2. Lead Optimization
3. Materials and Methods
3.1. Chemistry
3.2. Synthesis
3.2.1. General Procedure A (Scheme 3)
3.2.2. General Procedure B (Scheme 4)
3.2.3. General Procedure C (Scheme 5)
3.2.4. General Procedure D (Scheme 6)
3.3. Antimalarial Assay against P. falciparum 3D7
3.4. Antiproliferative Assay against MCF-7
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Structure | Consensus Log P | LogS (ESOL) | Pharmacokinetics | Lead-Likeness | Synthetic Tractability | ||||
---|---|---|---|---|---|---|---|---|---|
GI Absorption | BBB Permeant | Pgp Substrate | CYP1A2 Inhibitor | CYP2C9 Inhibitor | |||||
2.71 | −3.97 | High | No | No | No | Yes | 1 violation: MW > 350 | 3.29 | |
2.39 | −3.83 | High | No | No | Yes | Yes | Yes | 2.54 | |
1.76 | −2.97 | High | No | No | No | No | Yes | 2.55 | |
2.08 | −3.28 | High | No | No | No | Yes | Yes | 3.07 | |
2.91 | −4.19 | High | No | No | No | Yes | 1 violation: MW > 350 | 3.4 | |
2.39 | −3.62 | High | No | No | No | Yes | 1 violation: MW > 350 | 3.18 | |
2.74 | −3.85 | High | No | No | Yes | Yes | 1 violation: MW > 350 | 3.29 | |
1.99 | −2.90 | High | No | No | No | No | Yes | 2.55 |
Compound | Structure | IC50 (µM) 3D7 ± SD |
---|---|---|
2 | 0.219 ± 0.024 | |
4 | >10 | |
5 | >10 | |
6 | >10 | |
7 | 3.25 ± 0.21 | |
8 | 0.586 ± 0.032 | |
9 | 1.11 ± 0.10 | |
10 | >10 |
Compound | IC50 (µM) 3D7 ± SD | IC50 (µM) MCF-7 | |
---|---|---|---|
2 | 0.219 ± 0.024 | 17.50 | |
18 | 0.607 ± 0.030 | >20 | |
19 | 2.886 ± 0.401 | >20 | |
20 | 1.407 ± 0.115 | >20 | |
21 | 0.036 ± 0.005 | >20 | |
22 | 0.360 ± 0.034 | >20 | |
23 | 0.038 ± 0.009 | 9.74 | |
24 | 0.022 ± 0.005 | >20 | |
25 | 0.711 ± 0.038 | 10.52 | |
26 | 0.406 ± 0.034 | >20 | |
27 | 0.059 ± 0.012 | >20 | |
28 | >10 | >20 | |
29 | >10 | >20 |
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Charoensutthivarakul, S.; Lohawittayanan, D.; Kanjanasirirat, P.; Jearawuttanakul, K.; Seemakhan, S.; Chabang, N.; Schlaeppi, P.; Tantivess, V.; Limboonreung, T.; Phanchana, M. Rational Design and Lead Optimisation of Potent Antimalarial Quinazolinediones and Their Cytotoxicity against MCF-7. Molecules 2023, 28, 2999. https://doi.org/10.3390/molecules28072999
Charoensutthivarakul S, Lohawittayanan D, Kanjanasirirat P, Jearawuttanakul K, Seemakhan S, Chabang N, Schlaeppi P, Tantivess V, Limboonreung T, Phanchana M. Rational Design and Lead Optimisation of Potent Antimalarial Quinazolinediones and Their Cytotoxicity against MCF-7. Molecules. 2023; 28(7):2999. https://doi.org/10.3390/molecules28072999
Chicago/Turabian StyleCharoensutthivarakul, Sitthivut, Duangporn Lohawittayanan, Phongthon Kanjanasirirat, Kedchin Jearawuttanakul, Sawinee Seemakhan, Napason Chabang, Patrick Schlaeppi, Varisa Tantivess, Tanapol Limboonreung, and Matthew Phanchana. 2023. "Rational Design and Lead Optimisation of Potent Antimalarial Quinazolinediones and Their Cytotoxicity against MCF-7" Molecules 28, no. 7: 2999. https://doi.org/10.3390/molecules28072999