Structural requirements of 3-carboxyl-4(1H)-quinolones as potential antimalarials from 2D and 3D QSAR analysis (original) (raw)
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2D, 3D-QSAR and molecular docking of 4(1H)-quinolones analogues with antimalarial activities
Journal of Molecular Graphics and Modelling, 2013
Cytochrome bc 1 has become a major focus as a molecular target in malaria parasites, which are the most important vector-borne infectious disease in the world. The inhibition of cytochrome bc 1 blocks the mitochondrial respiratory chain and the consequent arrest of pyrimidine biosynthesis, which is essential for parasite development. The authors developed a theoretical study of two-dimensional, three-dimensional quantitative structure-activity relationships and a docking analysis of a series of 4(1H)-quinolones acting as cytochrome bc 1 inhibitors. The predictive ability of the quantitative structure-activity relationship models was assessed using internal (leave-one-out cross-validation) and external (test set with 8 compounds) validation. From the two-dimensional quantitative structure-activity relationship models, the authors emphasized the following descriptors: GCUT SLOGP 0, SLogP VSA 5, Kier molecular flexibility index, electrophilicity index, the partition coefficient and the charge of atom 5 of the quinolone ring as the most important to explain the antimalarial activity of the compounds studied. Three-dimensional quantitative structure-activity relationship models showed that the substituents R1 and R4 in 4(1H)-quinolones analogues are key modulators to enhance the antimalarial activity. The appropriate binding conformations and orientations of these compounds interacting with cytochrome bc 1 were also revealed by molecular docking. Based on the established models, 8 new compounds with highly predicted antimalarial activity have been theoretically designed and presented as a reference for synthesis and antimalarial evaluation.
Indian Journal of Chemistry -Section B (IJC-B), 2021
In the present article, k nearest neighbour molecular field analysis (kNN-MFA) method was used to develop a three dimensional quantitative structure activity relationship (3D-QSAR) model. In this study 37 derivatives of quinoxaline having antimalarial activity were used. Sphere exclusion (SE) algorithm was used to create the biological activity data set in to into training and test set. For model generation kNN-MFA method has coupled with stepwise, simulated annealing and genetic algorithm this method provides various models, in which the most significant model developed by stepwise backward-forward method with predictive internal q 2 =0.7589 and external predictivity (pred_r 2 = 0.4752). In the presented model electrostatic descriptors play crucial role for activity. Electrostatic descriptor (E_137) indicates regions in which electron withdrawing groups are favourable and descriptor (E_939) represents electron rich or electron donating groups are advantageous in particular region. The counter map/ plot of this model further helps to understand the relationship of structural feature of derivative of quinoxaline and its biological activity this would be applied for designing of new potent antimalarial containing quinoxaline as lead.
2D and 3D QSAR studies of novel Quinazoline derivatives for their potent Antimalarial activity
Two-dimensional (2D) and three-dimensional (3D) quantitative structure activity relationship (QSAR) studies have been carried out on a series of 63 compounds having quinazoline ring to find out the structural requirements of DHFR inhibitors for their antimalarial activity. In 2D QSAR, PLS regression coupled with stepwise forward-backward variable selection method resulted with r2, q2 and pred_r2 values of 0.8531, 0.7361 and 0.7003 respectively. The best predictions were obtained from the model where 43 compounds were considered in the training set and 17 in the test set. The best model for 3D-QSAR has been obtained with q2=0.5303 and pred r2=0.5255 when k-NN method coupled with stepwise forward backward variable selection was used. The results that are obtained from 2D and 3D QSAR studies may provide useful substitution patterns on the quinazoline skeleton and may also help to design more potent compounds. http://jprsolutions.info
QSAR and Ab Initio studies of quinolon-4(1H)-imine derivatives as antimalarial agents
Acta Chimica Asiana, 2021
Malaria is still the most dangerous disease threat in the world, including in Indonesia. In Indonesia, it is estimated that there are 20 million cases of malaria per year. Malaria resistance to conventional drugs requires the search for new antimalarial drugs. Molecular modeling can be a solution to these problems. An activity study of 22 quinolone-4 (1H) -imine derivatives as antimalarials was carried out using the QSAR Quantitative Structure-Activity Relationship method. The electronic and molecular descriptors were obtained from the Hartree-Fock HF / 6-31G ab initio calculation. The multiple linear regression (MLR) method was used to construct the QSAR model. The best QSAR models produced are: pEC50 = -4,177 + (37,902 x qC3) + (171,282 x qC8) + (9,061 x qC10) + (125,818 x qC11) + (-149,125 x qC17) + (191,623 x qC18), with statistical parameters, n = 22; r2 = 0,910; SEE = 0,171; Fhit/Ftab = 4,510 dan PRESS = 0,697. The best QSAR equation model can be used as a reference for design...
Structural Chemistry, 2012
A series of 53 endochin analogs (4(1-H)quinolone derivatives) with anti-malarial activity against the clinically relevant multidrug resistant malarial strain TM-90-C2B has been studied. The CORAL (http://www.insi lico.eu/coral) software has been used as a tool to build up the quantitative structure-activity relationships (QSAR) for the anti-malaria activity. The QSAR models were calculated with the representation of the molecular structure by simplified molecular input-line entry system and by the molecular graph of atomic orbitals. The method for splitting data into the sub-training set, the calibration set, the test set, and the validation set is suggested. Three various splits were examined. Statistical quality of models for the validation sets (which are not involved in the building up models) is good. Structural indicators (alerts) for increase and decrease of the anti-malaria activity are defined.
QSAR Analysis of 7-Substituted 4-Aminoquinolines for Designing Potent Antimalarial Agents
The emergence and rapid spread of chloroquine resistant strains of Plasmodium falciparum has dramatically reduced the chemotherapeutic options. Towards this goal, the quantitative structureactivity relationship analyses of some synthesized 7-substituted 4-aminoquinolines were performed for their antiplasmodial activity against chloroquine-resistant parasites to find out the structural features responsible for the biological activity. The statistically significant best 2D QSAR model having correlation coefficient (r 2) = 0.8631 and cross validated squared correlation coefficient (q 2) = 0.8101 with external predictive ability (pred_r 2) = 0.6740 was developed by Partial Least Square Regression coupled with stepwise backward-forward method using Vlife MDS 3.5 software and showed that the parameters Average-ve potential, T_2_N_5, XcompDipole and QMDipoleX were highly correlated with antiplasmodial activity of 7-substituted 4-aminoquinolines. The all developed models are interpretable, with good statistical and predictive significance, and can be used for guiding ligand modification for the development of potential new antimalarial agents.
Optimization of endochin-like quinolones for antimalarial activity
Experimental Parasitology, 2011
Structural analogs of the antimalarial Endochin were synthesized and screened for antiplasmodial activity against drug sensitive and multidrug resistant strains of Plasmodium falciparum. Structural features have been identified that are associated with improved potency while other features are associated with equipotency against an atovaquone-resistant clinical isolate. Relative to endochin the most active compound ELQ-121 shows ≈ 100-fold improvement in IC 50 for inhibition of P. falciparum in vitro and it also exhibits enhanced metabolic stability. A polyethylene glycol carbonate ester prodrug of ELQ-121 demonstrated in vivo efficacy against P. yoelii in mice. This is the first report of an endochin-like quinolone that is efficacious in treating malaria in a mammalian host.
The Journal of Engineering and Exact Sciences, 2019
Quantitative structure–activity relationships (QSAR) has been a reliable study in the development of models that predict biological activities of chemical substances based on their structures for the development of novel chemical entities. This study was carried out on 44 compounds of 4-amidinoquinoline and 10-amidinobenzonaphthyridine derivatives to develop a model that relates their structures to their activities against Plasmodium falciparum. Density Functional Theory (DFT) with basis set B3LYP/6-31G∗ was used to optimize the compounds. Genetic Function Algorithm (GFA) was employed in selecting descriptors and building the model. Four models were generated and the model with best internal and external validation has internal squared correlation coefficient (
Discovery, Synthesis, and Optimization of Antimalarial 4(1H)-Quinolone-3-Diarylethers
Journal of Medicinal Chemistry, 2014
The historical antimalarial compound endochin served as a structural lead for optimization. Endochin-like quinolones (ELQ) were prepared by a novel chemical route and assessed for in vitro activity against multidrug resistant strains of Plasmodium falciparum and against malaria infections in mice. Here we describe the pathway to discovery of a potent class of orally active antimalarial 4(1H)-quinolone-3-diarylethers. The initial prototype, ELQ-233, exhibited low nanomolar IC 50 values against all tested strains including clinical isolates harboring resistance to atovaquone. ELQ-271 represented the next critical step in the iterative optimization process, as it was stable to metabolism and highly effective in vivo. Continued analoging revealed that the substitution pattern on the benzenoid ring of the quinolone core significantly influenced reactivity with the host enzyme. This finding led to the rational design of highly selective ELQs with outstanding oral efficacy against murine malaria that is superior to established antimalarials chloroquine and atovaquone.
European Journal of Medicinal Chemistry, 2004
A widely applicable three-dimensional QSAR pharmacophore model for antimalarial activity was developed from a set of 17 substituted antimalarial indolo[2,1-b]quinazoline-6,12-diones (tryptanthrins) that exhibited remarkable in vitro activity (below 100 ng/mL) against sensitive and multidrug-resistant Plasmodium falciparum malaria. The pharmacophore, which contains two hydrogen bond acceptors (lipid) and two hydrophobic (aromatic) features, was found to map well onto many well-known antimalarial drug classes including quinolines, chalcones, rhodamine dyes, Pfmrk cyclin dependent kinase inhibitors, malarial FabH inhibitors, and plasmepsin inhibitors. The phamacophore allowed searches for new antimalarial candidates from multiconformer 3D databases and enabled custom designed synthesis of new potent analogues.