Comparative Molecular Field Analysis Research Articles

A novel antiparasitic medicine from coumarins against Dactylogyrus intermedius infection in goldfish using 3D-QSAR model

Dactylogyrus is one of the most serious parasites in aquaculture, resulting in devastating disease for severe economic impacts. In order to further increase the anthelmintic activity of coumarins, statistically valid three-dimensional quantitative structure-activity relationship (3D-QSAR) models was conducted by comparative molecular field analysis (CoMFA) to obtain better novel and promising anthelmintic coumarins within a total of 52 compounds in this study. By served C24 and C41 as template molecules, the steric and electrostatic fields of comparative molecular field analysis (CoMFA) showed a good correlation and predictive power, which was verified the model reliable. Based on the models, eight newly coumarin derivatives Q1-Q8 were designed and synthesized, and Q1, Q2, Q6 and Q7 showed better antiparasitic activities (the EC50 values ranged from 0.18 to 0.26 mg/L) than that of coumarin C24 and C41 (the EC50 values of 0.85 and 0.80 mg/L). By comparing the therapeutic index (TI), the order is the potency of Q4 > Q5 > Q7 > mebendazole >Q2 > Q6 > praziquantel >Q1 > Q3, which suggests that Q4 should be a viable way for controlling Dactylogyrus infection. Meanwhile, Q4 with a high stability in aquacultural water in immersion suppressed horizontal transmission of Dactylogyrus. These results will be contributed to further improve drug potency on aquacultural parasite control.

In silico Prediction of Novel SARS-CoV 3CL pro Inhibitors: a Combination of 3D-QSAR, Molecular Docking, ADMET Prediction, and Molecular Dynamics Simulation

The Chymotrypsin-like protease (3CLpro) is a drug target in the coronavirus because of its role in processing the polyproteins that are translated from the viral RNA. This study applied 3D quantitative structure-activity relationship (3D-QSAR), molecular docking, and ADMET prediction on a series of SARS-CoV 3CLpro inhibitors. The 3D-QSAR study was applied using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) methods, which gave the cross-validation coefficient (Q2) values of 0.64 and 0.80, the determination coefficient (R2) values of 0.998 and 0.993 and the standard error of the estimate (SEE) values of 0.046 and 0.091, respectively. The acceptable values of the determination coefficient (R2 test) to CoMFA and CoMSIA respectively corresponding to values of 0.725 and 0.690 utilizing a test set of seven molecules prove the high predictive ability of this model. Molecular docking analysis was utilized to validate 3D-QSAR methods and explain the binding site interactions and affinity between the most active ligands and the SARS-CoV 3CLpro receptor. Based on these results, a novel series of compounds were predicted, and their pharmacokinetic properties were verified using drug-likeness and ADMET prediction. Finally, the best-docked candidate molecules were subjected to molecular dynamics (MD) simulation to affirm their dynamic behavior and stability.

Discovery of Novel Chromone Derivatives Containing a Sulfonamide Moiety as Anti-ToCV Agents through the Tomato Chlorosis Virus Coat Protein-Oriented Screening Method.

A number of novel chromone derivatives containing sulfonamide moieties were designed and synthesized, and the activity of compounds against tomato chlorosis virus (ToCV) was assessed using the ToCVCP-oriented screening method. Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models were established based on the dissociation constant (Kd) values of the target compounds, and compound 35 was designed and synthesized with the aid of CoMFA and CoMSIA models. The study of affinity interaction indicated that compound 35 exhibited excellent affinity with ToCVCP with a Kd value of 0.11 μM, which was better than that of the positive control agents xiangcaoliusuobingmi (0.44 μM) and ningnanmycin (0.79 μM). In addition, the in vivo inhibitory effect of compound 35 on the ToCVCP gene was evaluated by the quantitative real-time polymerase chain reaction. ToCVCP gene expression levels of the compound 35 treatment group were reduced by 67.2%, which was better than that of the positive control agent ningnanmycin (59.5%). Therefore, compound 35 can be used as a potential anti-ToCV drug in the future.

3D-QSAR and molecular docking studies of 4-methyl quinazoline derivatives as PI3Kα inhibitors

A new series of 4- methyl quinazoline derivatives was synthesized and its anti-cancer activity was assessed. It was revealed that its compounds have potent inhibition on related phosphoinositide 3-kinases alpha (PI3Kα). In this study, the three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular docking approaches were performed on a series of 4-methyl quinazoline derivatives with PI3Kα inhibitors. The 3D-QSAR study was applied using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) methods, which gave the cross-validation coefficient (Q2) values of 0.850 and 0.92, the determination coefficient (R2) values of 0.998 and 0.987, and the standard error of the estimate (SEE) values of 0.017 and 0.105, respectively. The acceptable values of determination coefficient (R2 test) to CoMFA and CoMSIA respectively corresponding to values of 0.793 and 0.804 utilizing a test set of seven molecules prove the high predictive ability of this model. Using AutoDock tools, Molecular docking analysis was utilized to validate 3D-QSAR methods and to explain the binding site interactions and energy between the most active ligands and the PI3Kα (PDB ID: 4JPS) receptor. Based on these results, a novel series of 4- methyl quinazoline derivatives was predicted.

Rationalization of the activity Profile of Pyruvate Kinase Isozyme M2 (PKM2) Inhibitors using 3D QSAR.

Pyruvate kinase isozyme M2 (PKM2) was observed to be overexpressed and play a key role in cell growth and cancer cells' metabolism. During the past years, phytochemicals have been developed as new treatment options for chemoprevention and cancer therapy. Natural resources, like shikonin (naphthoquinone) and its derivatives, have emerged to be high potential therapeutics in cancer treatment. Our study aimed to design novel anti-tumour agents (PKM2 inhibitors) focusing on the shikonin scaffold with a better activity using computational methods. We applied a three-dimensional quantitative structure-activity relationship (3D-QSAR) approach using Field-based QSAR. The Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were performed on a series of forty shikonin derivatives, including shikonin, to develop robust models and rationalize the PKM2 inhibitory activity profile by building a correlation between structural features and activity. These predictive computational models will further help the design and synthesis of potent PKM2 inhibitors and their fast biological assessment at a low cost.

Development of 3D-QSAR models for predicting the activities of chemicals to stimulate muscle growth via β2-adrenoceptor

β2-adrenoceptor (β2AR) agonists can stimulate skeletal muscle growth. Their illegal use in food-producing animals, human athletes and bodybuilders causes adverse health effects. In the present study, we developed 3D-QSAR models for predicting the activity of chemicals which can stimulate skeletal muscle growth through β2AR. The activity of 25 β2AR agonists was measured by β2AR-cAMP response element (CRE) –luciferase (Luc) reporter assay. The 3D-QSAR models were built using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The CoMFA and CoMSIA models displayed high external predictability (R2 0.996 and 0.992, respectively) and good statistical robustness, and revealed that electrostatic effects were the most prominent forces influencing the activity of β2AR agonists. The CoMFA and CoMSIA contour plots provided clues regarding the main chemical features responsible for the activity variations and also resulted in predictions which correlate very well with the observed activity. In vitro study with differentiated myotubes showed that the potency orders of β2AR agonists in activating the β2AR-CRE-Luc reporter and in upregulating CREB target genes related to muscle growth were consistent. These 3D-QSAR models provide tools for predicting the activity of chemicals which might be illegally used in livestock or humans to stimulate skeletal muscle growth.

Dose-effect and structure-activity relationships of haloquinoline toxicity towards Vibrio fischeri.

Many quinoline (QL) derivatives are present in the environment and pose potential threats to human health and ecological safety. The acute toxicity of 30 haloquinolines (HQs) was examined using the photobacterium Vibrio fischeri. IC50 values (inhibitory concentration for 50% luminescence elimination) were in the range 5.52 to >200 mg·L-1. The derivative 5-BrQL exhibited the highest toxicity, with 3-ClQL, 3-BrQL, 4-BrQL, 5-BrQL, 6-BrQL, and 6-IQL all having IC50 values below 10 mg·L-1. Comparative molecular field analysis modeling based on the steric and electrostatic field properties of the HQs was used to quantify the impact of halogen substituents on their toxicity. QL derivative rings with larger substituents at the 2/8-positions and less negative charge at the 4/5/6/8-positions were positively correlated with acute toxicity towards V. fischeri.

Studies on molecular mechanism between SHP2 and pyridine derivatives by 3D-QSAR, molecular docking and MD simulations

BackgroundSrc homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) as a major phosphatase would affect the development of tumors by regulating several cellular processes, and is a significant potential target for cancer treatment. MethodsIn the present work, a series of pyridine derivatives possessing a wide range of inhibitory activity was employed to investigate the structural requirements by developing three dimensional quantitative structure–activity relationship (3D-QSAR) models using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. The results show that CoMFA (R2cv = 0.646, R2pred = 0.5587) and CoMSIA (R2cv = 0.777, R2pred = 0.7131) have excellent stability and predictability. The relationship between the inhibitory activity and structure of the inhibitors was analyzed by the derived contour maps. Furthermore, the QSAR models were validated by molecular docking and molecular dynamics simulations, which were also applied to reveal the potential molecular mechanism of these inhibitors. FindingsIt was found that Arg110, Asn216, Thr218, Thr252 and Pro490 play a crucial role in stabilizing the inhibitors. Additionally, MM/PBSA calculations provided the binding free energy were also conducted to explain the discrepancy of binding activities. Overall, the outcomes of this work could provide useful information and theoretical guidance for the development of novel and potent SHP2 inhibitors.

Quantitative Structure-Activity Relationships of Natural-Product-Inspired, Aminoalkyl-Substituted 1-Benzopyrans as Novel Antiplasmodial Agents.

On the basis of the finding that various aminoalkyl-substituted chromene and chromane derivatives possess strong and highly selective in vitro bioactivity against Plasmodium falciparum, the pathogen responsible for tropical malaria, we performed a structure–activity relationship study for such compounds. With structures and activity data of 52 congeneric compounds from our recent studies, we performed a three-dimensional quantitative structure–activity relationship (3D-QSAR) study using the comparative molecular field analysis (CoMFA) approach as implemented in the Open3DQSAR software. The resulting model displayed excellent internal and good external predictive power as well as good robustness. Besides insights into the molecular interactions and structural features influencing the antiplasmodial activity, this model now provides the possibility to predict the activity of further untested compounds to guide our further synthetic efforts to develop even more potent antiplasmodial chromenes/chromanes.

Novel Pyrazole-4-acetohydrazide Derivatives Potentially Targeting Fungal Succinate Dehydrogenase: Design, Synthesis, Three-Dimensional Quantitative Structure-Activity Relationship, and Molecular Docking.

Succinate dehydrogenase inhibitors (SDHIs) have emerged in fungicide markets as one of the fastest-growing categories that are widely applied in agricultural production for crop protection. Currently, the structural modification focusing on the flexible amide link of SDHI molecules is being gradually identified as one of the innovative strategies for developing novel highly efficient and broad-spectrum fungicides. Based on the above structural features, a series of pyrazole-4-acetohydrazide derivatives potentially targeting fungal SDH were constructed and evaluated for their antifungal effects against Rhizoctonia solani, Fusarium graminearum, and Botrytis cinerea. Strikingly, the in vitro EC50 values of constructed pyrazole-4-acetohydrazides 6w against R. solani, 6c against F. graminearum, and 6f against B. cinerea were, respectively, determined as 0.27, 1.94, and 1.93 μg/mL, which were obviously superior to that of boscalid against R. solani (0.94 μg/mL), fluopyram against F. graminearum (9.37 μg/mL), and B. cinerea (1.94 μg/mL). Concurrently, the effects of the substituent steric, electrostatic, hydrophobic, and hydrogen-bond fields on structure-activity relationships were elaborated by the reliable comparative molecular field analysis and comparative molecular similarity index analysis models. Subsequently, the practical value of pyrazole-4-acetohydrazide derivative 6w as a potential SDHI was ascertained by the relative surveys on the in vivo anti-R. solani preventative efficacy, inhibitory effects against fungal SDH, and molecular docking studies. The present results provide an indispensable complement for the structural optimization of antifungal leads potentially targeting SDH.

Designing of the N-ethyl-4-(pyridin-4-yl)benzamide based potent ROCK1 inhibitors using docking, molecular dynamics, and 3D-QSAR.

Rho-associated kinase-1 (ROCK1) has been recognized for its pivotal role in heart diseases, different types of malignancy, and many neurological disorders. Hyperactivity of ROCK phosphorylates the protein kinase-C (PKC), which ultimately induces smooth muscle cell contraction in the vascular system. Inhibition of ROCK1 has been shown to be a promising therapy for patients with cardiovascular disease. In this study, we have conducted molecular modeling techniques such as docking, molecular dynamics (MD), and 3-Dimensional structure-activity relationship (3D-QSAR) on a series of N-ethyl-4-(pyridin-4-yl)benzamide-based compounds. Docking and MD showed critical interactions and binding affinities between ROCK1 and its inhibitors. To establish the structure-activity relationship (SAR) of the compounds, 3D-QSAR techniques such as Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were used. The CoMFA (q2 = 0.774, r2 = 0.965, ONC = 6, and n}{}{r}_{pred}^{2} = 0.703) and CoMSIA (q2 = 0.676, r2 = 0.949, ONC = 6, and n}{}{r}_{pred}^{2} = 0.548) both models have shown reasonable external predictive activity, and contour maps revealed favorable and unfavorable substitutions for chemical group modifications. Based on the contour maps, we have designed forty new compounds, among which, seven compounds exhibited higher predictive activity (pIC50). Further, we conducted the MD study, ADME/Tox, and SA score prediction using the seven newly designed compounds. The combination of docking, MD, and 3D-QSAR studies helps to understand the coherence modification of existing molecules. Our study may provide valuable insight into the development of more potent ROCK1 inhibitors.

In silico analysis of 3D QSAR and Molecular Docking studies to discover new thiadiazole-thiazolone derivatives as mitotic kinesin Eg5 inhibition

A series of twenty one thiadiazole-thiazolone derivatives which is a class of highly potent human mitotic kinesin Eg5 inhibitor reported from published article were studied through a series of computer-aided drug design processes such as three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling, including comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) and Surflex-docking method using 17 compounds as training set. Both models showed good statistical quality and satisfying predictive ability (Q 2 = 0.617 and R 2 =0.919 for CoMFA ) and (Q 2 = 0.638 and R 2 =0.919 for CoMSIA ). The aim of this study was to explore 3D-QSAR approaches to propose new thiadiazole-thiazolone derivatives as Eg5 inhibitors for human mitotic kinesin. The CoMFA/CoMSIA contour maps were generated to provide the information about regions where the activity might be increased or decreased. Moreover, Based on the X-ray crystallized complex (PDB ID: 2UYM) molecular docking was performed on the most potent proposed Eg5 inhibitors using Surflex-dock method as an approach to investigate the stability of docked conformation and study the binding interactions in detail.

Insight into the structural requirement of aryl sulphonamide based gelatinases (MMP-2 and MMP-9) inhibitors – Part I: 2D-QSAR, 3D-QSAR topomer CoMFA and Naïve Bayes studies – First report of 3D-QSAR Topomer CoMFA analysis for MMP-9 inhibitors and jointly inhibitors of gelatinases together

ABSTRACT Gelatinases [gelatinase A – matrix metalloproteinase-2 (MMP-2), gelatinase B – matrix metalloproteinase-9 (MMP-9)] play key roles in many disease conditions including cancer. Despite some research work on gelatinases inhibitors both jointly and individually had been reported, challenges still exist in achieving potency as well as selectivity. Here in part I of a series of work, we have reported the structural requirement of some arylsulfonamides. In particular, regression-based 2D-QSARs, topomer CoMFA (comparative molecular field analysis) and Bayesian classification models were constructed to refine structural features for attaining better gelatinase inhibitory activity. The 2D-QSAR models exhibited good statistical significance. The descriptors nsssN, SHBint6, SHBint7, PubchemFP629 were directly correlated with the MMP-2 binding affinities whereas nsssN, SHBint10 and AATS2i were directly proportional to MMP-9 binding affinities. The topomer CoMFA results indicated that the steric and electrostatic fields play key roles in gelatinase inhibition. The established Naïve Bayes prediction models were evaluated by fivefold cross validation and an external test set. Furthermore, important molecular descriptors related to MMP-2 and MMP-9 binding affinities and some active/inactive fragments were identified. Thus, these observations may be helpful for further work of aryl sulphonamide based gelatinase inhibitors in future.

Docking-based 3D-QSAR, molecular dynamics simulation studies and virtual screening of novel ONC201 analogues targeting Mitochondrial ClpP

The human ClpP proteolytic complex is highly expressed in many types of solid and nonsolid cancers and has become a promising target for anticancer agents. In recent years, small molecules with various structures targeting ClpP have been reported. These include ONC201 and its derivatives ONC212 and the TR compounds. Here we report the binding interaction modes of a series of tetrahydropyrido[4,3-d]pyrimidine-2,4-diones ClpP-activing compounds using molecular docking, and three-dimensional quantitative structure activity relationships (3D-QSAR). Comparative molecular field analysis (CoMFA q2 = 0.862, r2 = 0.983) and topomer comparative molecular field analysis (Topomer CoMFA q2 = 0.905, r2 = 0.979) were used to establish 3D-QSAR models, which had good verification and prediction capabilities. Based on the contour maps and the information of molecular docking, 4 novel small molecules were designed and subjected to further molecular dynamics simulations (MD). The calculation of binding free energy showed that the residues ARG-78, LEU-79, GLU-82, ILE-84, HIS-116, TYR-118, TRP-146, LEU-104, PHE-105 and SER-108 of ClpP played a key role. The hydrogen bond analysis showed that SER108, TYR118, TRP146, GLU82 form stable hydrogen bonds with ClpP agonists. The MD results indicated that compound 93 could stably bind with the ClpP and might be a promising ClpP agonist candidate. The studies verified the specific binding mode of enzyme agonists through molecular docking and molecular dynamics simulations, and provided theoretical guidance for the design of new ONC201 analogues as ClpP agonists.

Molecular modeling studies of [4-(3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-amine-based CDK4 inhibitors.

Aim: CDK4 is a promising target for breast cancer therapy. This study aimed to explore the structure-activity relationship of CDK4 inhibitor abemaciclib analogs and design potent CDK4 inhibitors for breast cancer treatment. Methods & results: A faithful 3D quantitative structure-activity relationship model was established by molecular docking, comparative molecular field analysis and comparative molecular similarity index analysis based on 56 abemaciclib analogs. Molecular dynamics simulation studies revealed the key residues of the interaction between CDK4 and inhibitors. Four novel inhibitors with satisfactory predicted binding affinity to CDK4 were designed. Conclusion: The 3D quantitative structure-activity relationship and molecular dynamics simulation studies provide valuable insight into the development of novel CDK4 inhibitors.

Integrated 3D-QSAR, molecular docking, and molecular dynamics simulation studies on 1,2,3-triazole based derivatives for designing new acetylcholinesterase inhibitors.

Alzheimer’s disease (AD) is a multifactorial and polygenic disease. It is the most prevalent reason for dementia in the aging population. A dataset of twenty-six 1,2,3-triazole-based derivatives previously synthetized and evaluated for acetylcholinesterase inhibitory activity were subjected to the three-dimensional quantitative structure-activity relationship (3D-QSAR) study. Good predictability was achieved for comparative molecular field analysis (CoMFA) (Q2 = 0.604, R2 = 0.863, rext2 = 0.701) and comparative molecular similarity indices analysis (CoMSIA) (Q2 = 0.606, R2 = 0.854, rext2 = 0.647). The molecular features characteristics provided by the 3D-QSAR contour plots were quite useful for designing and improving the activity of acetylcholinesterase of this class. Based on these findings, a new series of 1,2,3-triazole based derivatives were designed, among which compound A1 with the highest predictive activity was subjected to detailed molecular docking and compared to the most active compound. The selected compounds were further subjected to 20 ns molecular dynamics (MD) simulations to study the comparative conformation dynamics of the protein after ligand binding, revealing promising results for the designed molecule. Therefore, this study could provide worthy guidance for further experimental analysis of highly effective acetylcholinesterase inhibitors.

Computational Modeling of Novel Phosphoinositol‐3‐kinase γ Inhibitors Using Molecular Docking, Molecular Dynamics, and 3D‐QSAR

Phosphoinositol‐3‐kinase γ (PI3Kγ) is a member of the class‐IB PI3K superfamily and plays a significant role in G‐protein‐coupled receptor mediated cell signaling. Recent studies have suggested that elevated expression of PI3Kγ in tumor‐associated macrophages strongly influences immune suppression and tumor growth. Due to the presence of many isoforms of PI3K, the selective inhibition of PI3Kγ remains challenging. Therefore, it is necessary to design more potent inhibitors against PI3Kγ for cancer treatment. In this study, we have reported the critical interactions of isoindolinone‐based inhibitors with PI3Kγ by docking and molecular dynamics simulations. The binding free energy of the receptor‐ligand complex was calculated using molecular mechanics/Poison‐Boltzmann surface area approach. We have performed the comparative molecular field analysis (CoMFA) and the comparative molecular similarity indices analysis (CoMSIA) to determine the structure–activity relationship of the inhibitors. The CoMFA (q2 = 0.681 and r2 = 0.968) and CoMSIA (q2 = 0.665 and r2 = 0.982) models showed reasonable predictive ability. Thereafter, the contour maps derived from CoMFA and CoMSIA were used to design several new compounds, among which, the compound D04 showed high predicted activity values. The designed compound was subjected to absorption‐distribution‐metabolism‐excretion/toxicity prediction and synthetic accessibility analyses. Our results could provide theoretical guidance for the future development of new PI3Kγ inhibitors.

Structural optimization for pyrimidine analogues inhibitors against MAP kinase interacting serine/threonine kinase 1(MNK1) based on molecular simulation

• A three-dimensional QSAR was insight into the structure-activity relationship of 4-aniline-thieno[2,3-d] pyrimidine derivatives (73compounds). • Steric, electrostatic, hydrophobic and hydrogen bond acceptor took into account simultaneously. • To understand the conformational stability and natural dynamics of the interaction in physiological environmental condition, compound 57/D1 and MNK1 were subjected to 100 ns MD simulation. • Theoretical calculations were carried out using density functional theory (DFT). • ADME property analysis also explored for in vivo applicability. MAP kinase interacting serine/threonine kinase 1 (MNK1) can promote the development of tumors through over-activation of MNK and phosphorylation of p-eIF4E, which is an important potential target for cancer therapy. A three-dimensional quantitative structure-activity relationship (3D-QSAR) is applied to investigate the relationship between activities and structures in this paper. Herein, a set of 73 4-aniline-thieno[2,3-d] pyrimidine derivatives were selected, and a 3D-QSAR study was performed by using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) model in this paper. The experimental results shown that CoMFA ( n = 10; q 2 = 0.765; r 2 = 0.979), CoMSIA ( n = 10; q 2 = 0.711; r 2 = 0.967) had good stability and predictability. The relationship between the activity and structure of the compound was analyzed by counter maps of the steric, electrostatic and hydrophobic fields. Subsequently, molecular docking was applied to explore key amino acids and docking modes at the active site. Based on the results, 10 new 4-aniline-thieno[2,3-d] pyrimidine derivatives were designed and their activities were predicted. Afterwards, these molecules were submitted to further ADME studies, in which the ADME properties of the 10 designed molecules were found to be within a reasonable range. Molecular Dynamics (MD) simulation analysis confirmed that the residues Leu55, Val63, Lys126, Leu127, Gly130, Ser131, Leu177, Phe192 play a vital role in the active site. In addition, these compounds mainly to bind to MNK1 through lipophilic interactions and hydrogen bonding. These results provided important reference to the discovery and design of new MNK1 inhibitors.

Anti-chronic myeloid leukemia activity and quantitative structure-activity relationship of novel thiazole aminobenzamide derivatives

The anti-chronic myeloid leukemia activity of thiazole aminobenzamide derivatives in vitro was tested by a methanethiosulfonate (MTS)-based viability assay method, and the result showed that some compounds exhibited good inhibitory activities against human chronic myeloid leukemia cell line K562, imatinib-resistant strain K562/R and T135I mutant cell line BaF3-ABL-BCR-T315I. Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) methods were used to analyze the relationship between the structure of thiazole aminobenzamide derivatives and the inhibition of K562/R cell activity. In CoMFA, Q2 was 0.899 and R2 was 0.963; in CoMSIA, Q2 and R2 were 0.840 and 0.903, respectively. These data indicated that the selected test set showed suitable external predictive ability. Combined with the contour map results, we further analyzed the three-dimensional quantitative structure (3D-QSAR) model. The results demonstrated that in the backbone of the thiazole aminobenzamide derivative, the substitution of a small group at R1 position, or the introduction of a hydrophilic group at R2 position, or the introduction of a large-volume amino acid at R3 position may be beneficial to improve the anti-CML activity of the compound.

Synthesis, antifungal activity and 3D-QSAR study of novel acyl thiourea compounds containing gem-dimethylcyclopropane ring.

A series of novel acyl thiourea compounds containing gem-dimethylcyclopropane ring were designed and synthesized by multi-step reactions in search of novel antifungal molecules. Structures of all the target compounds were characterized by spectral techniques of UV-vis, FT-IR, 1H-NMR, 13C-NMR, and ESI-MS. The antifungal activity of the target compounds was preliminarily evaluated by agar dilution method. The antifungal bioassay revealed that, at 50μg/mL, compounds 5h (R = o-F), 5m (R = p-Br), and 5n (R = o-NO2) showed the same antifungal activity of 73.6% against Physalospora piricola, which was comparable than that of the positive control. Furthermore, against Gibberella zeae, compounds 5k (R = m-Cl), 5l (R = m-Br), 5m (R = p-Br), and 5n (R = o-NO2) displayed the same antifungal activity of 75.6%, and compound 5o (R = p-NO2) displayed antifungal activity of 78.8%, which were all better than that of the positive control. The preliminary analysis of 3D-QSAR model was performed to study the effect of molecular structure on biological activity using the comparative molecular field analysis (CoMFA) method. The results showed 3D-QSAR model (r2 = 0.995, q2 = 0.503) was reasonable and effective.