Substituents R1 Research Articles

Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity. Part 4.

This project describes the synthesis, pharmacological and pharmacodynamic tests on two series of novel derivatives of 2H-pyrido[1,2-c]pyrimidine with potential binary binding to 5-HT1A receptors and SSRI + serotonin transporters. The influence of piperidinyl-indole (8.1-8.7) and tetrahydropyridinyl-indole (8.8-8.32) residues and indole 5-position substituents (R3 = Br, Cl, F) present in the pharmacophore element of ligands on their binding to both molecular targets was tested. A considerable impact of piperidinyl-indole residue on binding to both targets was confirmed and compounds with a high binding affinity were identified: Ki 5-HT1A = 12.4 nM; Ki SERT = 15.6 nM 8.1; Ki 5-HT1A = 5.6 nM; Ki SERT = 20.7 nM 8.7, while the presence of a tetrahydropyridinyl-indole residue was found to reduce the affinity of ligands to 5-HT1AR. The presence of chlorine (R3) in this series resulted in a notable reduction in binding to both targets (5-HT1A and SERT). Selected compounds had their metabolic stability in a first-pass test (human liver microsomes, NADPH) determined in vitro, and R1 and R2 substituents present on the terminal residue of pyrido[1,2-c]pyrimidine were recognized as having an impact on stability.

2-[(2,6-Dioxocyclohexyl)methyl]cyclohexane-1,3-dione 유도체의 Tyrosinase 저해활성에 관한 2D-QSAR 분석

기질 분자로서 2-[(2,6-dioxocyclohexyl)methyl]cyclohexane-1,3-dione 유도체(1-23)들의 분자 내 치환기(<TEX>$R_1$</TEX> 및 <TEX>$R_2$</TEX>)가 변화함에 따른 tyrosinase 수용체의 저해활성에 관한 2D-QSAR 모델로부터 다음과 같은 결론을 얻었다. 유도된 최적의 2D-QSAR 모델은 <TEX>$Obs.pI_{50}=-0.295({\pm}0.031)TDM$</TEX> <TEX>$-0.120({\pm}0.014)DMZ+0.135({\pm}0.050)DMX$</TEX>. <TEX>$R_2+6.382({\pm}0.17)$</TEX>이었으며, 예측성(<TEX>$q^2=0.843$</TEX>)보다는 상관성(<TEX>$r^2=0.905$</TEX>)이 큰 모델이었다. Tyrosinase 저해활성은 TDM > <TEX>$DMX.R_2{\geq}DMZ$</TEX> 순으로 영향을 미치었으며, 기질분자의 소수성(ClogP > 0)이 크고, <TEX>$R_1$</TEX>-치환기의 입체적 크기가 클수록 더욱 증가하는 경향을 나타내었다. 모델을 분석한 결과, 분자 내 <TEX>$R_2$</TEX>-치환기 상 X-축 성분의 쌍극자능률(<TEX>$DMX.R_2$</TEX>)이 클수록, 그리고 분자 전체의 쌍극자능률(TDM; Total Dipole Moment)과 Z-성분의 쌍극자능률(DMZ; Dipole Moment of Z-Component)이 작을수록 기질분자의 tyrosinase 저해활성이 높아짐을 암시하였다. 따라서 tyrosinase 저해활성은 기질분자 및 <TEX>$R_2$</TEX>-치환기의 전자 친화력에 기인한 것으로 예상되었다. 그러므로 저해활성을 증가시키려면 분자 내 극성 그룹을 소수성에 기여하는 비극성 작용기로 대체함이 바람직할 것으로 예측되었다. The following conclusion was made from the 2D-QSAR model for the tyrosinase inhibitory activity according to the variation of the substituents R1 and R2 in analogues of compound 2-[(2,6-dioxocyclohexyl)methyl]cyclohexane- 1,3-dione (1-23). The best optimized 2D-QSAR model was <TEX>$Obs.pI_{50}=-0.295({\pm}0.031)TDM$</TEX> <TEX>$-0.120({\pm}0.014)DMZ+0.135({\pm}0.050)DMX.R_2+6.382({\pm}0.17)$</TEX>, and the correlation <TEX>$r^2=0.905$</TEX>) of which was greater than its predictability (<TEX>$q^2=0.843$</TEX>). The magnitude of the effect of tyrosinase inhibitory activities was in order of TDM > <TEX>$DMX.R_2{\geq}DMZ$</TEX>, and it tended to increase as the hydrophobicity of substrate molecule (ClogP > 0) as well as the steric favor of substituent <TEX>$R_1$</TEX> increased. The analysis of the model implies that inhibitory activity of substrate molecule will increase as <TEX>$DMX.R_2$</TEX> (Dipole moment X component of <TEX>$R_2$</TEX>-substituent) increases, while TDM (Total Dipole Moment) and DMZ(Dipole Moment of Z-Component) decrease. As such, it is deemed feasible to conclude, that in order to increase the inhibitory effect, it would be rather desirable to replace the polar groups within the molecules with non-polar functional groups.

Synthesis and vasorelaxation evaluation of novel biphenyl–furocoumarin derivatives

A series of novel biphenyl–furocoumarin derivatives were synthesized and evaluated for their vasorelaxant activities in vitro against rat mesenteric artery, basilar artery, and renal artery ring models pre-contracted by high KCl. The results showed that compounds 12b, 13b, 13d, 14b, and 14d exhibited good broad spectrum vasorelaxant activities on three kinds of rat artery ring models compared to imperatorin. Noteworthy, most of the compounds had potent good selectivity against mesenteric artery in which compound 14c exhibited highest vasodilation activity (pEC50 = 6.44, Emax = 105.8 %). These were suggested that the introduction of biphenyl in imperatorin was useful to improve vasodilation activities. The preliminary structure–activity relationships studies revealed that larger halogen substituent R1 on phenyl ring and smaller nitrogenous base R2 were favorable for vasorelaxant activities. In addition, the CoMFA model showed acceptable correlative and predictive abilities (r2 = 0.875, q2 = 0.502).

Probing the origins of aromatase inhibitory activity of disubstituted coumarins via QSAR and molecular docking.

This study investigated the quantitative structure-activity relationship (QSAR) of imidazole derivatives of 4,7-disubstituted coumarins as inhibitors of aromatase, a potential therapeutic protein target for the treatment of breast cancer. Herein, a series of 3,7- and 4,7-disubstituted coumarin derivatives (1-34) with R1 and R2 substituents bearing aromatase inhibitory activity were modeled as a function of molecular and quantum chemical descriptors derived from low-energy conformer geometrically optimized at B3LYP/6-31G(d) level of theory. Insights on origins of aromatase inhibitory activity was afforded by the computed set of 7 descriptors comprising of F10[N-O], Inflammat-50, Psychotic-80, H-047, BELe1, B10[C-O] and MAXDP. Such significant descriptors were used for QSAR model construction and results indicated that model 4 afforded the best statistical performance. Good predictive performance were achieved as verified from the internal (comprising the training and the leave-one-out cross-validation (LOO-CV) sets) and external sets affording the following statistical parameters: R (2) Tr = 0.9576 and RMSETr = 0.0958 for the training set; Q (2) CV = 0.9239 and RMSECV = 0.1304 for the LOO-CV set as well as Q (2) Ext = 0.7268 and RMSEExt = 0.2927 for the external set. Significant descriptors showed correlation with functional substituents, particularly, R1 in governing high potency as aromatase inhibitor. Molecular docking calculations suggest that key residues interacting with the coumarins were predominantly lipophilic or non-polar while a few were polar and positively-charged. Findings illuminated herein serve as the impetus that can be used to rationally guide the design of new aromatase inhibitors.

ATRP/OMRP/CCT interplay in styrene polymerization mediated by iron(II) complexes: A DFT study of the α-diimine system.

A DFT study of various model systems has addressed the interference of catalytic chain transfer (CCT) as a function of the R(2) substituent in the atom-transfer radical polymerization (ATRP) of styrene catalyzed by [FeCl2 (R(1) N=C(R(2))C(R(2))=NR(1))] complexes. All model systems used R(1) =CH3 in place of the experimental Cy and tBu substituents and 1-phenylethyl in place of the polystyrene (PS) chain. A mechanistic investigation of 1) ATRP activation, 2) radical trapping in organometallic-mediated radical polymerization (OMRP), and 3) pathways to the hydride CCT intermediate was conducted with a simplified system with R(2)=H. This study suggests that CCT could occur by direct hydrogen-atom transfer without any activation barrier. Further analysis of more realistic models with R(2)=p-C6 H4 F or p-C6 H4 NMe2 suggests that the electronic effect of the aryl para substituents significantly alters the ATRP activation barrier. Conversely, the hydrogen-atom-transfer barrier is essentially unaffected. Thus, the greater ATRP catalytic activity of the p-NMe2 system makes the background CCT process less significant. The DFT study also compares the [FeCl2 (R(1) N=C(R(2))=C(R(2))=NR(1))] systems with a diaminobis(phenolato) derivative for which the CCT process shows even greater accessibility but has less incidence because of faster ATRP chain growth and interplay with a more efficient OMRP trapping. The difference between the two systems is attributed to destabilization of the Fe(II) catalyst by the geometric constraints of the tetradentate diaminobis(phenolato) ligand.

Effects of Some New Alkoxysilane External Donors on Propylene Polymerization in MgCl2-Supported Ziegler–Natta Catalysis

Five new alkoxysilanes with different sizes of hydrocarbon substituents were first synthesized and employed as external donors for propylene polymerization with a Ziegler–Natta catalyst. The effects of these and industrial alkoxysilanes with different sizes of hydrocarbon substituents on the microstructure of polypropylene were studied by SSA and 13C NMR. The results showed that isotactic sequence length of polypropylene increased with the size of R2 substituent on alkoxysilanes in the five donor systems, similar to the regularity of molecular weight, isotacticity, and thermal properties of polypropylene. Although the polypropylene produced by double cycloalkane substituents on alkoxysilanes had lower lamellae thickness L1, its contents were the highest. Moreover, excess large volume of hydrocarbon substituents on alkoxysilanes might be detrimental to improving isotactic sequence length of polypropylene. Polypropylene prepared by MIPDMS had a more uniform distribution of the stereodefects, indicating that MIPDMS might be used for the industrial production of BOPP.

Gas-transport properties of new mixed matrix membranes based on addition poly(3-trimethylsilyltricyclononene-7) and substituted calixarenes

Herein we report the results of the preparation and investigation of gas permeation parameters of novel membrane composite materials based on highly permeable addition poly(3-trimethylsilyltricyclononene-7) (PTCNSi1) and different substituted calixarenes (CA). Calix[4]arene and calix[8]arene with substituents R1 (R1=Me, Et, SiMe3) in the lower rim and R2 (R2=tert-Bu, H) in the upper rim were used as the additives. We explored the correlations between the structure of fillers (calixarenes) and gas permeation parameters of the composites. It is shown that the introduction of calixarenes results in increases in the separation factors, though a decrease in the observed permeability coefficients is observed. Thus, the addition of calix[4]arene with R1=Et and R2=tert-Bu increases the separation factors for H2/N2 gas pair more than twice, from 5.2 to 11.4, while the permeability coefficient P(H2) decreases from 2060 to 1000 Barrer. The increase of calixarene content tends to further enhance the separation factors. The application of positron annihilation lifetime spectroscopy indicated that these changes can be explained by certain reduction of mean size of free volume elements in the compositions containing calixarenes. The data of BET, TEM, WAXD, and mechanical properties of the composites are also reported and discussed.

New series of monoamidoxime derivatives displaying versatile antiparasitic activity

Following the promising antileishmanial results previously obtained in monoamidoxime series, a new series of derivatives was synthesized using manganese(III) acetate, Wittig reactions and Suzuki–Miyaura cross coupling reactions. Pharmacomodulation in R1, R2 or R3 substituents on the amidoxime structure is shown to influence antiprotozoan activity in vitro: a monosubstituted phenyl group in R1 (32–35) led to an activity against Leishmania donovani promastigotes (32, IC50 = 9.16 μM), whereas a polysubstituted group (36–37) led to an activity against Plasmodium falciparum (36, IC50 = 2.76 μM). Modulating chemical substituents in R2 and R3 only influenced the antiplasmodial activity in vitro. This suggests that the amidoxime scaffold has properties that could make it a promising new antiparasitic pharmacophore.

Synthesis and biological evaluation of thienopyrimidine derivatives as GPR119 agonists

A series of thienopyrimidine derivatives was synthesized and evaluated for their GPR119 agonistic ability. Several thienopyrimidine derivatives containing R1 and R2 substituents displayed potent GPR119 agonistic activity. Among them, compound 5d, which is a prototype, showed good in vitro activity with an EC50 value of 3nM and human and rat liver microsomal stability. Compound 5d exhibited no CYP inhibition and induction, Herg binding, or mutagenic potential. Compound 5d showed increase insulin secretion in beta TC-6 cell and lowered the glucose excursion in mice in an oral glucose-tolerance test.

Enantioselective Diamination with Novel Chiral Hypervalent Iodine Catalysts

Vicinal diamines constitute one the most important functional motif in organic chemistry because of its wide occurrence in a variety of biological and pharmaceutical molecules. We report an efficient metal‐free, highly stereoselective intramolecular diamination using a novel chiral hypervalent iodine reagent together with its application as an efficient catalyst for the synthesis of diamines.

Experimental evidence for competitive N[sbnd]O and O[sbnd]C bond homolysis in gas-phase alkoxyamines

The extensive use of alkoxyamines in controlled radical polymerisation and polymer stabilisation is based on rapid cycling between the alkoxyamine (R1R2NOR3) and a stable nitroxyl radical (R1R2NO•) via homolysis of the labile OC bond. Competing homolysis of the alkoxyamine NO bond has been predicted to occur for some substituents leading to production of aminyl and alkoxyl radicals. This intrinsic competition between the OC and NO bond homolysis processes has to this point been difficult to probe experimentally. Herein we examine the effect of local molecular structure on the competition between NO and OC bond cleavage in the gas phase by variable energy tandem mass spectrometry in a triple quadrupole mass spectrometer. A suite of cyclic alkoxyamines with remote carboxylic acid moieties (HOOCR1R2NOR3) were synthesised and subjected to negative ion electrospray ionisation to yield [M−H]− anions where the charge is remote from the alkoxyamine moiety. Collision-induced dissociation of these anions yield product ions resulting, almost exclusively, from homolysis of OC and/or NO bonds. The relative efficacy of NO and OC bond homolysis was examined for alkoxyamines incorporating different R3 substituents by varying the potential difference applied to the collision cell, and comparing dissociation thresholds of each product ion channel. For most R3 substituents, product ions from homolysis of the OC bond are observed and product ions resulting from cleavage of the NO bond are minor or absent. A limited number of examples were encountered however, where NO homolysis is a competitive dissociation pathway because the OC bond is stabilised by adjacent heteroatom(s) (e.g. R3=CH2F). The dissociation threshold energies were compared for different alkoxyamine substituents (R3) and the relative ordering of these experimentally determined energies is shown to correlate with the bond dissociation free energies, calculated by ab initio methods. Understanding the structure-dependent relationship between these rival processes will assist in the design and selection of alkoxyamine motifs that selectively promote the desirable OC homolysis pathway.

Catalytic Formation of Five-Membered Zirconacycloallenoids and Their Reaction with Carbon Dioxide

Hydrozirconation of phenylacetylene followed by a reaction with ((trimethylsilyl)ethynyl)lithium gave the respective (σ-alkenyl)(σ-alkynyl)zirconocene complex 6a. Its treatment with a catalytic amount of B(C6F5)3 (2 mol %) at room temperature resulted in efficient σ-ligand coupling with the formation of the isomeric five-membered zirconacycloallenoid complex 9a. Two similar examples with different substituents R1 (SiMe3, tBu) were also investigated. All three new zirconacycloallenoids (9a–c) were characterized by X-ray diffraction. The addition reaction of carbon dioxide to the zirconacycloallenoid complex 9c and two related examples from the literature were studied. The carbon dioxide addition products were also characterized by X-ray crystal structure analysis.

Elucidating the structural basis of diphenyl ether derivatives as highly potent enoyl-ACP reductase inhibitors through molecular dynamics simulations and 3D-QSAR study.

Diphenyl ether derivatives are good candidates for anti-tuberculosis agents that display a promising potency for inhibition of InhA, an essential enoyl-acyl carrier protein (ACP) reductase involved in fatty acid biosynthesis pathways in Mycobacterium tuberculosis. In this work, key structural features for the inhibition were identified by 3D-QSAR CoMSIA models, constructed based on available experimental binding properties of diphenyl ether inhibitors, and a set of four representative compounds was subjected to MD simulations of inhibitor-InhA complexes for the calculation of binding free energies. The results show that bulky groups are required for the R1 substituent on the phenyl A ring of the inhibitors to favor a hydrophobic pocket formed by residues Phe149, Met155, Pro156, Ala157, Tyr158, Pro193, Met199, Val203, Leu207, Ile215, and Leu218. Small substituents with a hydrophilic property are required at the R3 and R4 positions of the inhibitor phenyl B rings to form hydrogen bonds with the backbones of Gly96 and Met98, respectively. For the R2 substituent, small substituents with simultaneous hydrophilic or hydrophobic properties are required to favor the interaction with the pyrophosphate moiety of NAD(+) and the methyl side chain of Ala198, respectively. The reported data provide structural guidance for the design of new and potent diphenyl ether-based inhibitors with high inhibitory activities against M. tuberculosis InhA.

1-Substituted-5-[(3,5-dinitrobenzyl)sulfanyl]-1H-tetrazoles and their isosteric analogs: A new class of selective antitubercular agents active against drug-susceptible and multidrug-resistant mycobacteria

In this work, a new class of highly potent antituberculosis agents, 1-substituted-5-[(3,5-dinitrobenzyl)sulfanyl]-1H-tetrazoles and their oxa and selanyl analogs, is described. The minimal inhibitory concentration (MIC) values reached 1 μM (0.36–0.44 μg/mL) against Mycobacterium tuberculosis CNCTC My 331/88 and 0.25–1 μM against six multidrug-resistant clinically isolated strains of M. tuberculosis. The antimycobacterial effects of these compounds were highly specific because they were ineffective against all eight bacterial strains and eight fungal strains studied. Furthermore, these compounds exhibited low in vitro toxicity in four mammalian cell lines (IC50 > 30 μM). We also examined the structure–activity relationships of the compounds, particularly the effects on antimycobacterial activity of the number and position of the nitro groups, the linker between tetrazole and benzyl moieties, and the tetrazole itself. Relatively high variability of substituent R1 on the tetrazole in the absence of negative effects on antimycobacterial activity allows further structural optimization with respect to toxicity and the ADME properties of the 1-substituted-5-[(3,5-dinitrobenzyl)sulfanyl]-1H-tetrazoles lead compounds.

Enantiomeric separation of functionalized ethano-bridged Tröger bases using macrocyclic cyclofructan and cyclodextrin chiral selectors in high-performance liquid chromatography and capillary electrophoresis with application of principal component analysis

The enantiomeric separation of a series of racemic functionalized ethano-bridged Tröger base compounds was examined by high performance liquid chromatography (HPLC) and capillary electrophoresis (CE). Using HPLC and CE the entire set of 14 derivatives was separated by chiral stationary phases (CSPs) and chiral additives composed of cyclodextrin (native and derivatized) and cyclofructan (derivatized). Baseline separations (Rs≥1.5) in HPLC were achieved for 13 of the 14 compounds with resolution values as high as 5.0. CE produced 2 baseline separations. The separations on the cyclodextrin CSPs showed optimum results in the reversed phase mode, and the LARIHC™ cyclofructan CSPs separations showed optimum results in the normal phase mode. HPLC separation data of the compounds was analyzed using principal component analysis (PCA). The PCA biplot analysis showed that retention is governed by the size of the R1 substituent in the case of derivatized cyclofructan and cyclodextrin CSPs, and enantiomeric resolution closely correlated with the size of the R2 group in the case of non-derivatized γ-cyclodextrin CSP. It is clearly shown that chromatographic retention is necessary but not sufficient for the enantiomeric separations of these compounds.

Reprint of: Enantiomeric separation of functionalized ethano-bridged Tröger bases using macrocyclic cyclofructan and cyclodextrin chiral selectors in high-performance liquid chromatography and capillary electrophoresis with application of principal component analysis.

The enantiomeric separation of a series of racemic functionalized ethano-bridged Tröger base compounds was examined by high performance liquid chromatography (HPLC) and capillary electrophoresis (CE). Using HPLC and CE the entire set of 14 derivatives was separated by chiral stationary phases (CSPs) and chiral additives composed of cyclodextrin (native and derivatized) and cyclofructan (derivatized). Baseline separations (Rs ≥ 1.5) in HPLC were achieved for 13 of the 14 compounds with resolution values as high as 5.0. CE produced 2 baseline separations. The separations on the cyclodextrin CSPs showed optimum results in the reversed phase mode, and the LARIHC cyclofructan CSPs separations showed optimum results in the normal phase mode. HPLC separation data of the compounds was analyzed using principal component analysis (PCA). The PCA biplot analysis showed that retention is governed by the size of the R1 substituent in the case of derivatized cyclofructan and cyclodextrin CSPs, and enantiomeric resolution closely correlated with the size of the R2 group in the case of non-derivatized γ-cyclodextrin CSP. It is clearly shown that chromatographic retention is necessary but not sufficient for the enantiomeric separations of these compounds.

Rational Perturbation of the Fluorescence Quantum Yield in Emission‐Tunable and Predictable Fluorophores (Seoul‐Fluors) by a Facile Synthetic Method Involving CH Activation

Fluorescence imaging enables the uniquely sensitive observation of functional‐ and molecular‐recognition events in living cells. However, only a limited range of biological processes have been subjected to imaging because of the lack of a design strategy and difficulties in the synthesis of biosensors. Herein, we report a facile synthesis of emission‐tunable and predictable Seoul‐Fluors, 9‐aryl‐1,2‐dihydrolopyrrolo[3,4‐b]indolizin‐3‐ones, with various R1 and R2 substituents by coinage‐metal‐catalyzed intramolecular 1,3‐dipolar cycloaddition and subsequent palladium‐mediated C—H activation. We also showed that the quantum yields of Seoul‐Fluors are controlled by the electronic nature of the substituents, which influences the extent of photoinduced electron transfer. On the basis of this understanding, we demonstrated our design strategy by the development of a Seoul‐Fluor‐based chemosensor 20 for reactive oxygen species that was not accessible by a previous synthetic route.

Conformational properties of propargyloxy-calix[4]arene tricarboxamides: NMR and DFT studies on the O-through-the-annulus rotation

The size limit of substituents allowing O-through-the-annulus rotation of substituted calix[4]arenes was further extended to the propargyloxy group in 24-propargyloxy-25,26,27-tris(N,N-dimethylcarbamoylmethoxy)-p-tert-butylcalix[4]arene by demonstrating its free but slow motion affording equilibrium between the partial cone and 1,2-alternate conformers. The effect of solvent and upper rim substituents R1 on the conformational inversion was investigated by means of 1H NMR. The rotational isomerisation of the parent (R1 = H) analogue could not unambiguously be detected. The experimental results were supported by comprehensive density functional theory studies.

RESOLUTION OF RACEMIC γ-SUBSTITUTED BUTENOLIDE DERIVATIVES USING A POLYSACCHARIDE TYPE STATIONARY PHASE BY HIGH PERFORMANCE LIQUID CHROMATOGRAPHY

The enantioseparation by immobilized polysaccharide-based chiral stationary phases has pronounced advantages due to its enhanced efficiency and universal solvent resistance. The newly synthesized γ-substituted butenolide derivatives, which showed good inhibitory activity against wide range of fungi, were successfully resolved on cellulose tris(3,5-dichlorophenylcarbamate) chiral stationary phase (Chiralpak IC) by high performance liquid chromatography (HPLC). The effects of mobile phase composition and column temperature were studied. The good resolution was achieved using a mobile phase composition of hexane and ethanol. Under optimal conditions, the resolutions of enantiomers of five compounds were 1.96, 1.66, 1.93, 1.72, and 2.03, respectively. For the butenolides derivatives, π–π interaction contributes to the retention rather than selectivity, resolution was dramatically changed corresponding to variation of ethanol content in the mobile phase. This suggests that the dominant chiral recognition is from hydrogen bonding interactions. With regard to the structure of the analytes, bulky R1 substituents and electron deficiency R2 substituents appear to favor stereoselective interaction.

2D, 3D-QSAR and molecular docking of 4(1H)-quinolones analogues with antimalarial activities

Cytochrome bc1 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 bc1 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 bc1 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 bc1 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.