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3D-QSAR studies of 4-aminoquinoline-pyrimidine hybrids as antimalarial inhibitors targeting wild-type P. falciparum dihydrofolate reductase
(2025-11-01)
Jitonnom, Jitrayut
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Jitonnom, Wijitra
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Tue-Ngeun, Panthip
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Saparpakorn, Patchreenart
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Hannongbua, Supa
Three-dimensional quantitative structure–activity relationship (3D-QSAR) was determined on a set of 4-aminoquinoline-pyrimidine hybrids to elucidate the 3D structural features affecting the antimalaria activity against wild-type Plasmodium falciparum dihydrofolate reductase (PfDHFR). Several combined analyses of comparative molecular field (CoMFA), comparative molecular similarity indices (CoMSIA) and noncovalent interaction (NCI) were carried out. The 3D descriptors capturing steric, electrostatic and hydrophobic features of molecules and their correlation with experimental activity were established (CoMFA; q2= 0.506, r2= 0.875, SEE = 0.227 and CoMSIA; q2= 0.614, r2= 0.871, SEE = 0.230). Key structural features are drawn from the models: The R1substituent prefers small, less steric groups, while the R2substituent favors larger, more sterically bulky hydrophobic groups. Introducing hydrogen bond acceptor and donor groups at R2and the N-substituted linkage enhances activity. The docking and NCI results revealed extensive hydrophobic interactions and its stabilization to the binding process of PfDHFR.
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3D-QSAR and molecular docking studies of peptide-hybrids as dengue virus NS2B/NS3 protease inhibitors
(2024-06-01)
Jitonnom, Jitrayut
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Meelua, Wijitra
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Tue-nguen, Panthip
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Saparpakorn, Patchreenart
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Hannongbua, Supa
Global warming and climate change have made dengue disease a global health issue. More than 50 % of the world's population is at danger of dengue virus (DENV) infection, according to the World Health Organization (WHO). Therefore, a clinically approved dengue fever vaccination and effective treatment are needed. Peptide medication development is new pharmaceutical research. Here we intend to recognize the structural features inhibiting the DENV NS2B/NS3 serine protease for a series of peptide-hybrid inhibitors (R<inf>1</inf>–R<inf>2</inf>-Lys-R<inf>3</inf>-NH<inf>2</inf>) by the 3D-QSAR technique. Comparative molecular field analysis (q2 = 0.613, r2 = 0.938, r2<inf>pred</inf> = 0.820) and comparative molecular similarity indices analysis (q2 = 0.640, r2 = 0.928, r2<inf>pred</inf> = 0.693) were established, revealing minor, electropositive, H-bond acceptor groups at the R<inf>1</inf> position, minor, electropositive, H-bond donor groups at the R<inf>2</inf> position, and bulky, hydrophobic groups at the R<inf>3</inf> position for higher inhibitory activity. Docking studies revealed extensive H-bond and hydrophobic interactions in the binding of tripeptide analogues to the NS2B/NS3 protease. This study provides an insight into the key structural features for the design of peptide-based inhibitors of DENV NS2B/NS3 protease.
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Comparison of feline and human immunodeficiency virus reverse transcriptase enzymes through chemical screening and computational analysis
(2024-05-01)
Thammajong, Phanicha
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Aiebchun, Thitinan
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Boonyarattanakalin, Kanokthip
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Gleeson, Duangkamol
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Pobsuk, Nattakarn
Feline immunodeficiency virus (FIV) is a common infection found in domesticated and wild cats worldwide. Despite the wealth of therapeutic understanding of the disease in humans, considerably less information exists regarding the treatment of the disease in felines. Current treatment relies on drugs developed for the related human immunodeficiency virus (HIV) and includes compounds of the popular non-nucleotide reverse transcriptase (NNRTI) class. This is despite FIV-RT being only 67% similar to HIV-1 RT at the enzyme level, increasing to 88% for the allosteric pocket targeted by NNRTIs. The goal of this project was to try to quantify how well the more extensive pharmacological knowledge available for human disease translates to felines. To this end we screened known NNRTIs and 10 diverse pyrimidine analogs identified virtually. We use this chemo-centric probe approach to (a) assess the similarity between the two related RT targets based on the observed experimental inhibition values, (b) try to identify more potent inhibitors at FIV, and (c) gain a better appreciation of the structure–activity relationships (SAR). We found the correlation between IC<inf>50</inf>s at the two targets to be strong (r2 = 0.87) and identified compound 1 as the most potent inhibitor of FIV with IC<inf>50</inf> of 0.030 μM ± 0.009. This compared to FIV IC<inf>50</inf> values of 0.22 ± 0.17 μM, 0.040 ± 0.010 μM and >160 μM for known anti HIV-1 RT drugs Efavirenz, Rilpivirine, and Nevirapine, respectively. This knowledge, along with an understanding of the structural origin that give rise to any differences could improve the way HIV drugs are repurposed for FIV.
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Computational design, synthesis and biological evaluation of PDE5 inhibitors based on N2,N4-diaminoquinazoline and N2,N6-diaminopurine scaffolds
(2022-12-15)
Somnarin, Thanachon
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Pobsuk, Nattakarn
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Chantakul, Ruttanaporn
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Panklai, Teerapap
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Temkitthawon, Prapapan
We report the synthesis, and characterization of twenty-nine new inhibitors of PDE5. Structure-based design was employed to modify to our previously reported 2,4-diaminoquinazoline series. Modification include scaffold hopping to 2,6-diaminopurine core as well as incorporation of ionizable groups to improve both activity and solubility. The prospective binding mode of the compounds was determined using 3D ligand-based similarity methods to inhibitors of known binding mode, combined with a PDE5 docking and molecular dynamics based-protocol, each of which pointed to the same binding mode. Chemical modifications were then designed to both increase potency and solubility as well as validate the binding mode prediction. Compounds containing a quinazoline core displayed IC<inf>50</inf>s ranging from 0.10 to 9.39 µM while those consisting of a purine scaffold ranging from 0.29 to 43.16 µM. We identified 25 with a PDE5 IC<inf>50</inf> of 0.15 µM, and much improved solubility (1.77 mg/mL) over the starting lead. Furthermore, it was found that the predicted binding mode was consistent with the observed SAR validating our computationally driven approach.
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Preparation, biological & cheminformatics-based assessment of N2,N4-diphenylpyrimidine-2,4-diamine as potential Kinase-targeted antimalarials
(2021-09-15)
Toviwek, Borvornwat
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Phuangsawai, Oraphan
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Konsue, Adchatawut
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Hannongbua, Supa
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Riley, Jennifer
Twenty eight new N2,N4-diphenylpyrimidine-2,4-diamines have been prepared in order to expand our understanding of the anti-malarial SAR of the scaffold. The aim of the study was to make structural modifications to improve the overall potency, selectivity and solubility of the series by varying the anilino groups attached to the 2- and 4-position. We evaluated the activity of the compounds against Plasmodium falciparum (Pf) 3D7, cytotoxicity against HepG2, % inhibition at a panel of 10 human kinases, solubility, permeability and lipophilicity, and human and rat in vitro clearance. 11 was identified as a potent anti-malarial with an IC<inf>50</inf> of 0.66 µM at the 3D7 strain and a selectivity (SI) of ~ 40 in terms of cytotoxicity against the HepG2 cell line. It also displayed low experimental logD<inf>7.4</inf> (2.27), reasonable solubility (124 µg/ml), good metabolic stability, but low permeability. A proteo-chemometric workflow was employed to identify putative Pf targets of the most promising compounds. Ligand-based similarity searching of the ChEMBL database led to the identification of most probable human targets. These were then used as input for sequence-based searching of the Pf proteome. Homology modelling and molecular docking were used to evaluate whether compounds could indeed bind to these targets with valid binding modes. In vitro biological testing against close human analogs of these targets was subsequently undertaken. This allowed us to identify potential Pf targets and human anti-targets that could be exploited in future development.
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New potent epitopes from Leptospira borgpetersenii for the stimulation of humoral and cell-mediated immune responses: Experimental and theoretical studies
(2021-01-01)
Tansiri, Yada
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Sritrakul, Tepyuda
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Saparpakorn, Patchreenart
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Boondamnern, Timporn
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Chimprasit, Aunlika
The rhKU_Sej_LRR_2271 protein is introduced as one of the leptospiral vaccine candidates since it contains the predicted immunogenic epitopes. The in-silico sequence and structural based analysis have been used in this study to analyze MHC class I and class II-restricted epitopes of the protein. Six epitope prediction programs were employed, which the epitopes with high prediction scores from each program were aligned. The 21 of potentially unrestrained epitopes with prediction scores above the cut-off value from at least two prediction programs were selected. The 3D-molecular modeling, docking, and molecular dynamic simulation were performed to evaluate the affinity binding between peptide-MHC complex and T-cell receptor. One promising epitope, which is 171-LLFLPLIKI, showed the potency in binding to both MHC class I and II alleles. Two newly designed peptides containing epitopes which can bind to over 3 of MHC alleles, LL17:171-LLFLPLIKILYVDRNKL-187 and SL19:209-SLNSGIKALPFNYEKLVNL-227, significantly increased interferon-gamma (IFNg)-producing specific T-cell responses in the rhKU_Sej_LRR_2271 immunized rabbits compared to nonimmunized rabbits. The LL17 peptide can also induce interferon-gamma-producing specific CD4+ T-cell responses in the immunized rabbits. For the evaluation of humoral immune responses, the immunized rabbits have a significantly greater amount of specific IgG in plasma than the nonimmunized rabbits. Ex-vivo study of T-cell responses in animal model using flow cytometry confirmed an accomplishment of the theoretically in-silico analysis for discovering potential T-cell epitopes of the protein. The results show that the rhKU_Sej_LRR_2271 protein containing promiscuous T-cell epitopes, which can induce both humoral and cell-mediated immune responses, is a prospective protein candidate for leptospiral vaccine development.
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Diptoindonesin D, a potent antibacterial activity against gram-positive bacteria, an inhibitor of penicillin-binding protein 2a from the stem bark of Shorea roxburghii G.Don
(2019-11-01)
Sudto, Kanokorn
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Saparpakorn, Patchreenart
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Tancharoen, Chompoonuch
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Phromyothin, Darinee
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Techasakul, Supanna
The emergence and spread of antimicrobial resistance (AMR) is a serious threat to public human health. The challenge now is an urgent need to new potent antibiotics combating AMR which can be an effective way to solve the crisis. A new potent antibacterial activity of diptoindonesin D, together with four known compounds as hopeafuran, α-viniferan, hopeahainol A and hopeahainol C were isolated from the stem bark of Shorea roxburghii G. Don in Khon Kaen province, Thailand. Diptoindonesin D were screened for antimicrobial activity and possesses significant activity minimum inhibitory concentrations (MIC) values of 4.68 and 9.37 μg/mL against Staphylococcus epidermidis and Staphylococcus aureus, respectively. The absolute configuration of diptoindonesin D were evaluated by circular dichroism (ECD) calculations. The ECD results indicated that the possible configuration of diptoindonesin D should be R-configuration. Furthermore, reverse docking was performed to identify the protein target of diptoindonesin D based on four scoring functions using GOLD program. This investigation is the first time that reveals interaction between diptoindonesin D and its binding with cell wall synthesis protein targets. The results highlighted that, penicillin-binding protein 2a (PBP2a), an antibacterial cell wall, might be the potential target for the binding of diptoindonesin D. The obtained results can be useful as a guideline for the development of effective diptoindonesin D as a PBP2a inhibitor.
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Elucidation of vasodilation response and structure activity relationships of N2,N4-disubstituted quinazoline 2,4-diamines in a rat pulmonary artery model
(2019-01-14)
Paracha, Tamkeen Urooj
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Pobsuk, Nattakarn
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Salaloy, Nattapas
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Suphakun, Praphasri
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Pekthong, Dumrongsak
Pulmonary arterial hypertension (PAH) is a rare and progressive disease arising from various etiologies and pathogenesis. PAH decreases life expectancy due to pulmonary vascular remodeling, elevation of mean pulmonary arterial pressure, and ultimately progresses to heart failure. While clinical treatments are available to reduce the associated symptoms, a complete cure has yet to be found. Phosphodiesterase-5 (PDE-5) inhibition has been identified as a possible intervention point in PAH treatment. The functional vasodilation response to N2,N4-diamino quinazoline analogues with differing PDE-5 inhibitory activities and varying physicochemical properties were assessed in both endothelium-intact and denuded rat pulmonary arteries to gain greater insight into their mode of action. All analogues produced vasorelaxant effects with EC50s ranging from 0.58 ± 0.22 µM to >30 µM. It was observed that vasodilation response in intact vessels was highly correlated with that of denuded vessels. The ~10% drop in activity is consistent with a loss of the nitric oxide mediated cyclic guanosine monophosphate (NO/cGMP) pathway in the latter case. A moderate correlation between the vasodilation response and PDE-5 inhibitory activity in the intact vessels was observed. Experimental protocol using the alpha-adrenergic (α<inf>1</inf>) receptor agonist, phenylephrine (PE), was undertaken to assess whether quinazoline derivatives showed competitive behavior similar to the α<inf>1</inf> receptor blocker, prazosin, itself a quinazoline derivative, or to the PDE-5 inhibitor, sildenafil. Competitive experiments with the α<inf>1</inf>-adrenergic receptor agonist point to quinazoline derivatives under investigation here act via PDE-5 inhibition and not the former. The pre-incubation of pulmonary arterial rings with quinazoline test compounds (10 µM) reduced the contractile response to PE around 40–60%. The most promising compound (9) possessed ~32 folds higher selectivity in terms of vasodilation to its mammalian A549 cell cytotoxicity. This study provides experimental basis for PDE-5 inhibition as the mode of action for vasodilation by N2,N4-diamino quinazoline analogues along with their safety studies that may be beneficial in the treatment of various cardiovascular pathologies.
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Design, synthesis and evaluation of N 2 ,N 4 -diaminoquinazoline based inhibitors of phosphodiesterase type 5
(2019-01-15)
Pobsuk, Nattakarn
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Paracha, Tamkeen Urooj
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Chaichamnong, Nattiya
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Salaloy, Nattapas
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Suphakun, Praphasri
We describe the design, synthesis and evaluation of a series of N 2 ,N 4 -diaminoquinazoline analogs as PDE5 inhibitors. Twenty compounds were prepared and these were assessed in terms of their PDE5 and PDE6 activity, ex-vivo vasodilation response, mammalian cytotoxicity and aqueous solubility. Molecular docking was used to determine the binding mode of the series and this was demonstrated to be consistent with the observed SAR. Compound 15 was the most active PDE5 inhibitor (IC <inf>50</inf> = 0.072 ± 0.008 µM) and exhibited 4.6-fold selectivity over PDE6. Ex-vivo assessment of 15 and 22 in a rat pulmonary artery vasodilation model demonstrated EC <inf>50</inf> s of 1.63 ± 0.72 µM and 2.28 ± 0.74 µM respectively.
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Synthesis, plasmodium falciparum inhibitory activity, cytotoxicity and solubility of n2,n4-disubstituted quinazoline-2,4-diamines
(2019-01-01)
Pobsuk, Nattakarn
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Suphakun, Praphasri
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Hannongbua, Supa
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Nantasenamat, Chanin
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Choowongkomon, Kiattawee
Background: Despite the development of extensive control strategies and treatment options, approximately 200 million malaria cases, leading to approximately 450,000 deaths, were reported in 2015. Due to issue of disease resistance, additional drug development efforts are needed to produce new, more effective treatments. Quinazoline-2,4-diamines were identified as anti-parasitic compounds over three decades ago and have remained of interest to date in industry and academia. Objective: An anti-malarial SAR evaluation of previously unreported N2,N4-disubstituted quina-zoline-2,4-diamines have been undertaken in this study. We have synthesized and evaluated new derivatives against P. falciparum in our attempt to better characterize their biological activity and overall physical properties. Method: The synthesis of N2,N4-disubstituted quinazoline-2,4-diamines inhibitors is reported along with activities in a radioactive labeled hypoxanthine incorporation assay against the f Plasmodium falciparum (Pf.) K1 strain. In addition, cytotoxicity was determined in the A549 and Vero cell lines using an MTT based. The aqueous solubility of key compounds was assessed at pH 7.4 using a shake flask-based approach. Results: We identified compounds 1 and 6p as sub µM inhibitors of P. falciparum, having equivalent anti-malarial activity to Chloroquine. Compounds 1 and 6m are low µM inhibitors of P. falciparum with improved cytotoxicity profiles. Compound 6m displayed the best balance between P. falciparum Inhibitory activity (2 µM) and cytotoxicity, displaying >49 fold selectivity over A549 and Vero cell lines. Conclusion: Twenty one N2,N4-Disubstituted Quinazoline-2,4-diamines have been prepared in our group and characterized in terms of their antimalarial activity, cytotoxicity and physical properties. Compounds with good activity and reasonable selectivity over mammalian cell lines have been identified. SAR analyses suggest further exploration is are necessary to improve the balance of P. falciparum Inhibitory activity, cytotoxicity and solubility.

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