Series Of Ligands Research Articles

Design, preparation and evaluation of different branched biotin modified liposomes for targeting breast cancer

A series of liposome ligands (Bio-Chol, Bio-Bio-Chol, tri-Bio-Chol and tetra-Bio-Chol) modified by different branched biotins that can recognize the SMVT receptors over-expressed in breast cancer cells were synthesized. And four liposomes (Bio-Lip, Bio-Bio-Lip, tri-Bio-Lip and tetra-Bio-Lip) modified by above mentioned ligands as well as the unmodified liposome (Lip) were prepared to study the targeting ability for breast cancer. The cytotoxicity study and apoptosis assay of paclitaxel-loaded liposomes showed that tri-Bio-Lip had the strongest anti-proliferative effect on breast cancer cells. The cellular uptake studies on mice breast cancer cells (4T1) and human breast cancer cells (MCF-7) indicated tri-Bio-Lip possessed the strongest internalization ability, which was 5.21 times of Lip, 2.60 times of Bio-Lip, 1.67 times of Bio-Bio-Lip and 1.17 times of tetra-Bio-Lip, respectively. Moreover, the 4T1 tumor-bearing BALB/c mice were used to evaluate the in vivo targeting ability. The data showed the enrichment of liposomes at tumor sites were tri-Bio-Lip > tetra-Bio-Lip > Bio-Bio-Lip > Bio-Lip > Lip, which were consistent with the results of in vitro targeting studies. In conclusion, increasing the density of targeting molecules on the surface of liposomes can effectively enhance the breast cancer targeting ability, and the branching structure and spatial distance of biotin residues may also have an important influence on the affinity to SMVT receptors. Therefore, tri-Bio-Lip could be a promising drug delivery system for targeting breast cancer.

Synthesis and catalytic activity of cationic dinuclear palladium (II) complexes supported by thioether ligands containing two di-(2-picolyl) amine arms

The design, synthesis and characterization of a series of dithioether ligands featuring two di-(2-picolyl)amine arms (2a–2d) and their corresponding cationic dinuclear palladium (II) complexes (3a–d) are reported. Crystal structures of ligand 2b and complexes 3b and 3d were determined by X-ray diffraction studies. The molecular structures of 3b and 3d display each of the two di-(2-picolyl)amine fragments coordinated to one palladium(II) atom in a (κ3-N,N,N) tridentate fashion and with the cationic metal centers displaying square-planar geometries. Weak interactions between the metal centers and the thioether fragments are observed. All bimetallic complexes 3a–d were tested as catalytic precursors in the Suzuki couplings of different o- or p-substituted iodo- or bromoaryls with boronic acids. The overall catalytic results indicate that complex 3b is the best precursor of the series demonstrating even more efficient performance compared to commercial palladium sources such as Pd(OAc)2 and the Nájera Catalysts.

Palladium (II) Complexes Containing 2-Phenylpyridine Derivatives: Synthesis, Molecular Structures, and Catalytic Activity for Suzuki–Miyaura Cross-Coupling Reactions

The preparation and characterization of a series of new 2-phenylpyridine derivative ligands consisting of 2-(R) pyridine (R = mesityl (L1), 2,6-dimethylphenyl (L2), o-tolyl (L3), m-tolyl (L4), p-tolyl (L5), o-methoxyphenyl (L6), and p-methoxyphenyl (L7)) and their Pd complexes [PdCl2L2] (L1–L7) is investigated using a combination of X-ray diffraction spectroscopy, GC-MS, and NMR. The crystal structures show that the Pd complexes adopt a square planar geometry, and the monodentate ligand is coordinated through the N donor of the pyridine ring to the Pd atom. The catalytic activities of the synthesized complexes are investigated. The square planar Pd complex trans-[(2-mesitylpy)2PdCl2)] shows a high efficiency in promoting Suzuki-Miyaura cross coupling in an aqueous solvent under aerobic conditions.

Theoretical Insights into Modification of Nitrogen-Donor Ligands to Improve Performance on Am(III)/Eu(III) Separation.

Nitrogen-donor ligands have been considered to be promising agents for separating trivalent actinides (An(III)) from lanthanides (Ln(III)). Thereinto, how to decorate these ligands for better extraction performance is urgent to design "perfect" separating extractants. In this work, we systematically explored a series of heterocyclic N-donor ligands (L1 = dipyridazino[4,3-c:3',4'-h]acridine, L2 = dipyridazino[3,4-a:4',3'-j]phenazine, L3 = 2,6-di(cinnolin-3-yl)pyridine)), as well as their substituted derivatives, and compared their extraction and complexation ability toward An(III) and Ln(III) ions by using quasi-relativistic density functional theory (DFT). We found that the pyridazine N atoms probably play a notable role in electron donation to metal cations by molecular orbital (MO) and bond order analyses. Besides, the calculated results clearly verified that these N-donor ligands possess higher coordination affinity toward Am(III) over Eu(III). The rigid ligands (L1 and L2) exhibit higher selective abilities for the Am(III)/Eu(III) separation compared with that of the flexible ligand (L3). For each ligand, the 1:2 (metal/ligand) extraction reaction is predicted to be most probable in the separation process. The introduction of an alkyl group on the lateral chain or an electron-donating group on the main chain gives rise to a better extraction performance of the ligands, and the CyMe4 or MeO substituted ligands show higher extraction and separation ability. Simultaneous introduction of CyMe4 and MeO groups can enhance the extraction ability of the ligand to metal ions, but the separating ability depends on the differences of the extraction capacity of An(III) and Ln(III). This work can help to gain a more in-depth understanding the selectivity differences of similar N-donor ligands and provide more theoretical insights into the design of novel extractants for An(III)/Ln(III) separation.

Transient States and Barriers from Molecular Simulations and the Milestoning Theory: Kinetics in Ligand-Protein Recognition and Compound Design.

This study presents a novel computational approach to study molecular recognition and binding kinetics for drug-like compounds dissociating from a flexible protein system. The intermediates and their free energy profile during ligand association and dissociation processes control ligand-protein binding kinetics and bring a more complete picture of ligand-protein binding. The method applied the milestoning theory to extract kinetics and thermodynamics information from running short classical molecular dynamics (MD) simulations for frames from a given dissociation path. High-dimensional ligand-protein motions (3N-6 degrees of freedom) during ligand dissociation were reduced by use of principal component modes for assigning more than 100 milestones, and classical MD runs were allowed to travel multiple milestones to efficiently obtain ensemble distribution of initial structures for MD simulations and estimate the transition time and rate during ligand traveling between milestones. We used five pyrazolourea ligands and cyclin-dependent kinase 8 with cyclin C (CDK8/CycC) as our model system as well as metadynamics and a pathway search method to sample dissociation pathways. With our strategy, we constructed the free energy profile for highly mobile biomolecular systems. The computed binding free energy and residence time correctly ranked the pyrazolourea ligand series, in agreement with experimental data. Guided by a barrier of a ligand passing an αC helix and activation loop, we introduced one hydroxyl group to parent compounds to design our ligands with increased residence time and validated our prediction by experiments. This work provides a novel and robust approach to investigate dissociation kinetics of large and flexible systems for understanding unbinding mechanisms and designing new small-molecule drugs with desired binding kinetics.

Conformational Changes in Alkyl Chains Determine the Thermodynamic and Kinetic Binding Profiles of Carbonic Anhydrase Inhibitors.

Thermodynamics and kinetics of protein-ligand binding are both important aspects for the design of novel drug molecules. Presently, thermodynamic data are collected with isothermal titration calorimetry, while kinetic data are mostly derived from surface plasmon resonance. The new method of kinITC provides both thermodynamic and kinetic data from calorimetric titration measurements. The present study demonstrates the convenient collection of calorimetric data suitable for both thermodynamic and kinetic analysis for two series of congeneric ligands of human carbonic anhydrase II and correlates these findings with structural data obtained by macromolecular crystallography to shed light on the importance of shape complementarity for thermodynamics and kinetics governing a protein-ligand binding event. The study shows how minute chemical alterations change preferred ligand conformation and can be used to manipulate thermodynamic and kinetic signatures of binding. They give rise to the observation that analogous n-alkyl and n-alkyloxy derivatives of identical chain length swap their binding kinetic properties at unchanged binding affinity.

In situ surface-enhanced Raman scattering shows ligand-enhanced hot electron harvesting on silver, gold, and copper nanoparticles

Hot carriers (electrons and holes) generated from the decay of localized surface plasmon resonances can take a major role in catalytic reactions on metal nanoparticles. By obtaining surface enhanced Raman scattering (SERS) spectra of p-aminothiophenol as product of the reduction of p-nitrothiophenol by hot electrons, different catalytic activity is revealed here for nanoparticles of silver, gold, and copper. As a main finding, a series of different ligands, comprising halide and non-halide species, are found to enhance product formation in the reduction reaction on nanoparticles of all three metals. A comparison with the standard electrode potentials of the metals with and without the ligands and SERS data obtained at different electrode potential indicate that the higher catalytic activity can be associated with a higher Fermi level, thereby resulting in an improved efficiency of hot carrier generation. The concept of such a ligand-enhanced hot electron reduction provides a way to make light-to-chemical energy conversion more efficient due to improved electron harvesting.

Impact of Different Automated Binding Pose Generation Approaches on Relative Binding Free Energy Simulations.

Relative binding free energy (RBFE) prediction methods such as free energy perturbation (FEP) are important today for estimating protein-ligand binding affinities. Significant hardware and algorithmic improvements now allow for simulating congeneric series within days. Therefore, RBFE calculations have an enormous potential for structure-based drug discovery. As typically only a few representative crystal structures for a series are available, other ligands and design proposals must be reliably superimposed for meaningful results. An observed significant effect of the alignment on FEP led us to develop an alignment approach combining docking with maximum common substructure (MCS) derived core constraints from the most similar reference pose, named MCS-docking workflow. We then studied the effect of binding pose generation on the accuracy of RBFE predictions using six ligand series from five pharmaceutically relevant protein targets. Overall, the MCS-docking workflow generated consistent poses for most of the ligands in the investigated series. While multiple alignment methods often resulted in comparable FEP predictions, for most of the cases herein, the MCS-docking workflow produced the best accuracy in predictions. Furthermore, the FEP analysis data strongly support the hypothesis that the accuracy of RBFE predictions depends on input poses to construct the perturbation map. Therefore, an automated workflow without manual intervention minimizes potential errors and obtains the most useful predictions with significant impact for structure-based design.

Design, synthesis and application of triazole ligands in suzuki miyaura cross coupling reaction of aryl chlorides

DFT calculations have been demonstrated to be a valuable tool for the mechanistic study of reaction which is difficult to acquire from pure experimental techniques. Structural, electronic and coordination aspects of synthesized triazole ligands were investigated theoretically by structure optimization on Gaussian 09 package by DFT approach at B3LYP/6-31G (d, p). HOMO-LUMO energy gaps correlated to its chemical reactivity and this information applied to interpret the role of ligand in the formation of ligand-metal complex. Electron rich environment around the triazole core stabilized the HOMO orbital and made these electrons available to form complex with Pd centre. The DFT calculations provide a plausible mechanism for the reaction that is consistent with the available experimental facts. A series of triazole ligands have been synthesized via efficient 1,3-dipolar cycloaddition of readily available azide and alkynes for coordination to Pd centre. Characterization of all the synthesized compounds was done by FTIR, 1H NMR, 13C NMR and HRMS. Their ligand-Pd complexes provided excellent yields in the Suzuki-Miyaura coupling reactions (up to 92% yield) of unactivated aryl chlorides. Ligand 4-(2,6-dimethoxyphenyl)-1-phenyl-1H-1,2,3-triazole (L2) was found to be most effective ligand because of electron donating 2,6 dimethoxy phenyl moiety attached to triazole ring at 4-position that facilitated the formation of electron rich ligand-catalyst complex. The complex favoured the oxidative addition step of Pd across the aryl chloride substrate and thus allowed for the development of highly active ligand-catalyst system for Suzuki reaction. During computational analysis, 4-(2,6-dimethoxyphenyl)-1-phenyl-1H-1,2,3-triazole (L2) also showed lowest band gap due to electron rich distribution pattern on the HOMO that are involve in ligand-Pd complex formation. Conclusively, these triazoles ligands were found to be more competent and attractive for palladium catalyst because of simplistic pathway for the synthesis of triazole motif and the ease of individual tuning of the substituents on triazole core or exocyclic to it.

The role of human in the loop: lessons from D3R challenge 4.

The rapid development of new machine learning techniques led to significant progress in the area of computer-aided drug design. However, despite the enormous predictive power of new methods, they lack explainability and are often used as black boxes. The most important decisions in drug discovery are still made by human experts who rely on intuitions and simplified representation of the field. We used D3R Grand Challenge 4 to model contributions of human experts during the prediction of the structure of protein-ligand complexes, and prediction of binding affinities for series of ligands in the context of absence or abundance of experimental data. We demonstrated that human decisions have a series of biases: a tendency to focus on easily identifiable protein-ligand interactions such as hydrogen bonds, and neglect for a more distributed and complex electrostatic interactions and solvation effects. While these biases still allow human experts to compete with blind algorithms in some areas, the underutilization of the information leads to significantly worse performance in data-rich tasks such as binding affinity prediction.

Design and synthesis of fluorescent ligands for the detection of cannabinoid type 2 receptor (CB2R)

The Cannabinoid 2 receptor, CB2R, belonging to the endocannabinoid system, ECS, is involved in the first steps of neurodegeneration and cancer evolution and progression and thus its modulation may be exploited in the therapeutic and diagnostic fields. However, CB2Rs distribution and signaling pathways in physiological and pathological conditions are still controversial mainly because of the lack of reliable diagnostic tools. With the aim to produce green and safe systems to detect CB2R, we designed a series of fluorescent ligands with three different green fluorescent moieties (4-dimethylaminophthalimide, 4-DMAP, 7-nitro-4-yl-aminobenzoxadiazole, NBD, and Fluorescein-thiourea, FTU) linked to the N1-position of the CB2R pharmacophore N-adamantyl-4-oxo-1,4-dihydroquinoline-3-carboxamide through polymethylene chains. Compound 28 emerged for its compromise between good pharmacodynamic properties (CB2R Ki = 130 nM and no affinity vs the other subtype CB1R) and optimal fluorescent spectroscopic properties. Therefore, compound 28 was studied through FACS (saturation and competitive binding studies) and fluorescence microscopy (visualization and competitive binding) in engineered cells (CB2R-HEK293 cells) and in diverse tumour cells. The fluoligand binding assays were successfully set up, and affinity values for the two reference compounds GW405833 and WIN55,212-2, comparable to the values obtained by radioligand binding assays, were obtained. Fluoligand 28 also allowed the detection of the presence and quantification of the CB2R in the same cell lines. The interactions of compound 28 within the CB2R binding site were also investigated by molecular docking simulations, and indications for the improvement of the CB2R affinity of this class of compounds were provided. Overall, the results obtained through these studies propose compound 28 as a safe and green alternative to the commonly used radioligands for in vitro investigations.

Do Gold(III) Complexes Form Hydrogen Bonds? An Exploration of AuIII Dicarboranyl Chemistry.

The reaction of 1,1'-Li2 [(2,2'-C2 B10 H10 )2 ] with the cyclometallated gold(III) complex (C^N)AuCl2 afforded the first examples of gold(III) dicarboranyl complexes. The reactivity of these complexes is subject to the trans-influence exerted by the dicarboranyl ligand, which is substantially weaker than that of non-carboranyl anionic C-ligands. In line with this, displacement of coordinated pyridine by chloride is only possible under forcing conditions. While treatment of (C^N)Au{(2,2'-C2 B10 H10 )2 } (2) with triflic acid leads to Au-C rather than Au-N bond protonolysis, aqueous HBr cleaves the Au-N bond to give the pyridinium bromo complex 7. The trans-influence of a series of ligands including dicarboranyl and bis(dicarboranyl) was assessed by means of DFT calculations. The analysis demonstrated that it was not sufficient to rely exclusively on geometric descriptors (calculated or experimental) when attempting to rank ligands for their trans influence. Complex (C^N)Au(C2 B10 H11 )2 containing two non-chelating dicarboranyl ligands was prepared similar to 2. Its reaction with trifluoroacetic acid also leads to Au-N cleavage to give trans-(Hpy^C)Au(OAcF )(C2 B10 H11 )2 (8). In crystals of 8 the pyridinium N-H bond points towards the metal centre, while in 7 it is bent away. The possible contribution of gold(III)⋅⋅⋅H-N hydrogen bonding in these complexes was investigated by DFT calculations. The results show that, unlike the situation for platinum(II), there is no evidence for an energetically significant contribution by hydrogen bonding in the case of gold(III).

A novel chiral surfactant-type metallomicellar catalyst for asymmetric Michael addition in water.

A series of Schiff-based ligands consisting of both tertiary amines and lipophilic groups were designed and synthesized. Using these ligands, a new chiral surfactant-type metallomicellar catalyst was developed in water, and this was identified by SEM/TEM analyses. These metallomicelles can be empolyed in asymmetric Michael addition reactions in water, delivering the corresponding adducts with excellent yields and enantioselectivities.

Palladium(II) complexes containing 2-phenylpyridine derivatives: synthesis, molecular structures, and catalytic activity for Suzuki—Miyaura cross-coupling reactions

The preparation and characterization of a series of new 2-phenylpyridine derivative ligands consisting of 2-(R) pyridine (R = mesityl (L1), 2,6-dimethylphenyl (L2), o-tolyl (L3), m-tolyl (L4), p-tolyl (L5), o-methoxyphenyl (L6), and p-methoxyphenyl (L7)) and their Pd complexes [PdCl2L2] (L1—L7) is investigated using a combination of X-ray diffraction spectroscopy, GC-MS, and NMR. The crystal structures show that the Pd complexes adopt a square planar geometry, and the monodentate ligand is coordinated through the N donor of the pyridine ring to the Pd atom. The catalytic activities of the synthesized complexes are investigated. The square planar Pd complex trans-[(2-mesitylpy)2PdCl2)] shows a high efficiency in promoting Suzuki—Miyaura cross coupling in an aqueous solvent under aerobic conditions.

Synthesis and antiproliferative activity of benzimidazole-based, trinuclear neutral cyclometallated and cationic, N^N-chelated ruthenium(ii) complexes.

A series of 2-phenyl and 2-pyridyl tris-benzimidazole ligands was reacted with the [Ru(p-cymene)Cl2]2 dimer to yield the corresponding neutral cyclometallated and cationic organoruthenium(ii) complexes. All of the synthesized compounds were characterized using an array of spectroscopic and analytical techniques, including 1H, 13C nuclear magnetic resonance (NMR), infrared spectroscopy and mass spectrometry. The trinuclear compounds were screened for their cytotoxicy against the MCF-7 breast cancer cell line and the triple negative MDA-MB-231 breast cancer cell line at concentrations of 10 and 20 μM. Overall, the 2-pyridyl ligands 10 and 11, and their corresponding trinuclear complexes [16][PF6]3 and [17][PF6]3, show the most promising activity as these compounds significantly reduce the percentage cell survival of MCF-7 and MDA-MB-231 breast cancer cell lines at the aforementioned fixed concentrations. It was observed that 10 and [16][PF6]3 show potency greater than that of cisplatin against the MCF-7 breast cancer cell line, and [17][PF6]3 shows potency comparable to that of cisplatin against the MCF-7 cell line. Additionally, the synthesized compounds were observed to have relatively low cytotoxicty towards MCF-12A breast epithelial cells and relatively higher selectivity towards MCF-7 breast cancer cells compared to cisplatin.

Chemical control of competing electron transfer pathways in iron tetracyano-polypyridyl photosensitizers.

Photoinduced intramolecular electron transfer dynamics following metal-to-ligand charge-transfer (MLCT) excitation of [Fe(CN)4(2,2′-bipyridine)]2− (1), [Fe(CN)4(2,3-bis(2-pyridyl)pyrazine)]2− (2) and [Fe(CN)4(2,2′-bipyrimidine)]2− (3) were investigated in various solvents with static and time-resolved UV-Visible absorption spectroscopy and Fe 2p3d resonant inelastic X-ray scattering (RIXS). This series of polypyridyl ligands, combined with the strong solvatochromism of the complexes, enables the 1MLCT vertical energy to be varied from 1.64 eV to 2.64 eV and the 3MLCT lifetime to range from 180 fs to 67 ps. The 3MLCT lifetimes in 1 and 2 decrease exponentially as the MLCT energy increases, consistent with electron transfer to the lowest energy triplet metal-centred (3MC) excited state, as established by the Tanabe–Sugano analysis of the Fe 2p3d RIXS data. In contrast, the 3MLCT lifetime in 3 changes non-monotonically with MLCT energy, exhibiting a maximum. This qualitatively distinct behaviour results from a competing 3MLCT → ground state (GS) electron transfer pathway that exhibits energy gap law behaviour. The 3MLCT → GS pathway involves nuclear tunnelling for the high-frequency polypyridyl breathing mode (hν = 1530 cm−1), which is most displaced for complex 3, making this pathway significantly more efficient. Our study demonstrates that the excited state relaxation mechanism of Fe polypyridyl photosensitizers can be readily tuned by ligand and solvent environment. Furthermore, our study reveals that extending charge transfer lifetimes requires control of the relative energies of the 3MLCT and the 3MC states and suppression of the intramolecular distortion of the acceptor ligand in the 3MLCT excited state.

Breaking the barrier: an osmium photosensitizer with unprecedented hypoxic phototoxicity for real world photodynamic therapy.

Hypoxia presents a two-fold challenge in the treatment of cancer, as low oxygen conditions induce biological changes that make malignant tissues simultaneously more aggressive and less susceptible to standard chemotherapy. This paper reports the first metal-based photosensitizer that approaches the ideal properties for a phototherapy agent. The Os(phen)2-based scaffold was combined with a series of IP-nT ligands, where phen = 1,10-phenanthroline and IP-nT = imidazo[4,5-f][1,10]phenanthroline tethered to n = 0-4 thiophene rings. Os-4T (n = 4) emerged as the most promising complex in the series, with picomolar activity and a phototherapeutic index (PI) exceeding 106 in normoxia. The photosensitizer exhibited an unprecedented PI > 90 (EC50 = 0.651 μM) in hypoxia (1% O2) with visible and green light, and a PI > 70 with red light. Os-4T was also active with 733 nm near-infrared light (EC50 = 0.803 μM, PI = 77) under normoxia. Both computation and spectroscopic studies confirmed a switch in the nature of the lowest-lying triplet excited state from triplet metal-to-ligand charge transfer (3MLCT) to intraligand charge transfer (3ILCT) at n = 3, with a lower energy and longer lifetime for n = 4. All compounds in the series were relatively nontoxic in the dark but became increasingly phototoxic with additional thiophenes. These normoxic and hypoxic activities are the largest reported to date, demonstrating the utility of osmium for phototherapy applications. Moreover, Os-4T had a maximum tolerated dose (MTD) in mice that was >200 mg kg-1, which positions this photosensitizer as an excellent candidate for in vivo applications.

Electron accepting naphthalene bisimide ligand architectures for modulation of π-π stacking in nanocrystal hybrid materials.

Investigation of charge transfer in quantum dot (QD) systems is an area of great interest. Specifically, the relationship between capping ligand and rate of charge transfer has been studied as a means to optimize these materials. To investigate the role of ligand interaction on the QD surface for electron transfer, we designed and synthesized a series of ligands containing an electron accepting moiety, naphthalene bisimide (NBI). These ligands differ in their steric bulk: as one allows for π-π stacking between the NBI moieties at high surface coverages, while the other does not, allowing for a direct comparison of these effects. Once grafted onto QDs, these hybrid materials were studied using UV-Vis, fluorescence, and transient absorption spectroscopy. Interestingly, the sample with the fastest electron transfer was not the sample with the most NBI π-π stacking, it was instead where these ligands were mixed amongst oleic acid, breaking up H-aggregates between the NBI groups.

Palladium(II) Complex with Tridentate Ligand Containing Pyrenyl Core

A series of ligands containing pyrenyl core which are PyEt1, PyEt2, and PyEt3 have been successfully synthesized. PyEt2, a bidentate ligand and PyEt3, a tridentate ligand were used to prepared Pd(II) complexes by reactions with PdCl2(CH3CN)2. The titled compounds displayed intriguing geometries around the central palladium atoms. 1H-NMR results showed that palladium in Pd-PyEt3 adopts a five-coordinate configuration.
 Keywords: Pyrene, palladium, five coordination.

Design of antimalarial agents based on pyrimidine derivatives as methionine aminopeptidase 1b inhibitor: Molecular docking, quantitative structure activity relationships, and molecular dynamics simulation studies

AbstractMalaria is a parasitic disease mainly caused by Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, and Plasmodium ovale and rarely by animal plasmodium such as Plasmodium knowlesi. Despite the worldwide endorsement of eradicating malaria, the mortality and morbidity of malaria is still high, especially in children of resource‐poor regions of the world. In the current study, a series of 2‐pyridyl pyrimidine derivatives with P. falciparum methionine aminopeptidase 1b (MA1b) inhibitory activity were subjected to quantitative structure, relationship activities, molecular docking, and molecular dynamics simulation to identify the ideal physicochemical characteristics and the drug–receptor interactions of potential antimalarial compounds. The structures were built using HyperChem. A docking study was performed using AutoDock. The obtained quantitative structure activity relationships model has showed that the descriptors MLOGP, E2p, Mor24u, PW2, and H8m mainly affect the antimalarial activity of the series of ligands. The residues His 277, Fe 370, Asp 240, Trp 320, and Tyr 260 of MA1b play a very important role in the drug–enzyme interaction by creating hydrogen bond, π‐cation, and π‐π interactions. To give a complete impression about the pyrimidine derivatives, compound 7 was subjected to 1,000 ps molecular dynamics (MD) simulations. The best structure based on our study was suggested for a future new drug with potential antimalarial compounds.