Abstract
Quantitative structure–activity relationship studies conducted on forty-five (45) derivatives of 2-anilino 4-amino substituted quinazolines as malaria inhibitors to determine the structures responsible for their antimalarial properties and design novel derivatives with improved activities. The molecular descriptors generated were selected to develop the theoretical model using the genetic approximation component of the material studio. The developed model found to be a function of ATSC8c, GATS8i, SpMin1_Bhi, JGI10, and TDB6u descriptors, shows excellent statistical parameters (R2 = 0.7913, R2adj = 0.7553, Q2cv = 0.7112, LOF = 0.2125, and R2pred = 0.7650). The mean effect (MF) analysis revealed the descriptor SpMin1_Bhi, as the most influential by its largest percentage contribution (54%) to the developed model. The descriptor decodes the information on the first ionization potentials and was found to have positive MF. Hence, activity increases with increases the descriptor value. Structural modifications of the template (compound 13; pEC50 = 7.387) using electron-withdrawing groups increases the descriptor value (first ionization potentials) of the template, which by extension increases the antimalarial activity lead to the design of ten (10) novel theoretical derivatives with improve antimalarial activities. Compound 3, N4-(3-bromo-5-fluorobenzyl)-N2-(4-fluorophenyl)-6,7-dimethoxyquinazoline-2,4-diamine was found to have the highest antimalarial activities among all the designed derivatives (pEC50 = 8.0515).
Highlights
Malarial has maintained its status as one of the most devastating diseases in evolving countries, which increases several socioeconomic challenges [3]
Estimated malaria casualty in the year 2017 is said to be in the region of 200 million infections worldwide leading to over 400 thousand death [10], with children in the age bracket of 5 years mostly affected [22]
The protozoan, Plasmodium consisting of five species of the renowned parasite (P. falciparum, P. vivax, P. malariae, P. ovale, and P. knowlesi) is the genesis of the contagious disease, with P. falciparum as the deadliest of the species [10]
Summary
Malarial has maintained its status as one of the most devastating diseases in evolving countries, which increases several socioeconomic challenges [3]. The protozoan, Plasmodium consisting of five species of the renowned parasite (P. falciparum, P. vivax, P. malariae, P. ovale, and P. knowlesi) is the genesis of the contagious disease, with P. falciparum as the deadliest of the species [10]. The uses of drugs for the treatment are not without its challenges, inform of the resistance of P. falciparum against the available antimalarial drugs. The optimization of novel antimalarial drugs using new target molecules, having the capacity of overcoming this resistance menace has become a most and urgent quest to embark [5]. Several compounds such as SN Applied Sciences (2021) 3:767
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