Synthesis and antiplasmodial structure-activity relationships for some novel 4-aminoquinolines and 5-chlorobenzimidazoles

Includes bibliographical references.Two novel 7-substituted 4-aminoalkylated quinolines, Nl,Nl-diethyl-N2-(7-trifuoromethylthio-4-quinolinyl)-1,2-ethanediamine 11 and Nt, Nl-diethyl-N2-(7-trifuoromethoxy-4-quinolinyl)-1,2-ethanediamine 12 were synthesized via a versatile 6-step route and their antiplasmodial activities against the chloroquine sensitive D10 strain of Plasmodium falciparum have been investigated in vitro. A quantitative structure activity analysis of these compounds showed an excellent correlation of log ICso, corrected for vacuolar accumulation, with log ß-haematin inhibitory activity when compared with known values for other analogues substituted at the 7 -position. The correlation showed a law accumulation-normalised ICso for 11, which suggests that it is the most potent antimalarial at the site of action of all of the analogues of this type. 11 and 12 however had relatively high observed IC50 values compared to the other analogues, which can be attributed to their low pKa1 values and subsequent low vacuolar accumulation in the parasite. In addition, the benzimidazole nucleus, which has similar dipolar character to 4-aminoquinoline nucleus, was investigated as alternative template for potential antimalarials. This involved the synthesis of the chloroquine-like analogues 2-(5-chlorobenzoimidazol-1-yl)-N-(2-diethylaminoethylethanamide 13, N-[2-(5-chlorobenzoimidazol-1-yl)ethyl]-2-( 4-methylpiperazin-1-yl)ethanamide 14 and N-[2-( 5-chlorobenzoimidazol-1-yl)ethyl]-N-[2-(4-methylpiperazin-1-yl)ethyl]amine 15. The latter two products were prepared by a regioselective route to 5-chlorobenzimidazoles. These compounds had poor activity against P. falciparum and none showed ß-haematin inhibitory activity although their precursor, 5-chloro-1 H-benzimidazole, had ß-haematin inhibitory activity. Their poor activity was ascribed to this lack of ß-haematin inhibitory activity as well as their low pKa which would result in poor vacuolar accumulation. Finally, the novel side chain N-(2-aminoethyl)-2-(4-methylpiperazin-1-yl)ethanamide 14b incorporated in 14 was coupled to a 7 -chloroquinoline nucleus in order to compare the 4-amino-7-chloroquinoline nucleus directly with the 5-chlorobenzimidazole nucleus. Thus, the analogous 4-aminoquinoline N-[2-(7-chloro- 4-quinolinyl)ethyl]-2-(4-methylpiperazin-1-yl)ethanamide 16 was synthesized. This compound retains anti-plasmodial activity, demonstrating that the lack of activity in 14 and 15 can be ascribed to the replacement of the quinoline nucleus with the benzimidazole nucleus and not to the side chain itself

SYNTHESIS AND BIOLOGICAL EVALUATION OF THE DERIVATIVES OF 1,3,5-TRIAZIN-2,4-DIONES AND THEIR FUSED ANALOGUES.

Ph.DDOCTOR OF PHILOSOPH

Meta-QSAR: a large-scale application of meta-learning to drug design and discovery.

We investigate the learning of quantitative structure activity relationships (QSARs) as a case-study of meta-learning. This application area is of the highest societal importance, as it is a key step in the development of new medicines. The standard QSAR learning problem is: given a target (usually a protein) and a set of chemical compounds (small molecules) with associated bioactivities (e.g. inhibition of the target), learn a predictive mapping from molecular representation to activity. Although almost every type of machine learning method has been applied to QSAR learning there is no agreed single best way of learning QSARs, and therefore the problem area is well-suited to meta-learning. We first carried out the most comprehensive ever comparison of machine learning methods for QSAR learning: 18 regression methods, 3 molecular representations, applied to more than 2700 QSAR problems. (These results have been made publicly available on OpenML and represent a valuable resource for testing novel meta-learning methods.) We then investigated the utility of algorithm selection for QSAR problems. We found that this meta-learning approach outperformed the best individual QSAR learning method (random forests using a molecular fingerprint representation) by up to 13%, on average. We conclude that meta-learning outperforms base-learning methods for QSAR learning, and as this investigation is one of the most extensive ever comparisons of base and meta-learning methods ever made, it provides evidence for the general effectiveness of meta-learning over base-learning

Supplementary data for article: Božić, A. R.; Filipović, N. R.; Verbić, T.; Milčić, M. K.; Todorović, T.; Cvijetić, I.; Klisurić, O.; Radišić, M.; Marinković, A. A Detailed Experimental and Computational Study of Monocarbohydrazones. Arabian Journal of Chemistry 2020. https://doi.org/10.1016/j.arabjc.2017.08.010

Supplementary material for: [https://www.sciencedirect.com/science/article/pii/S1878535217301661?via%3Dihub]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/318

Assessing Physicochemical Properties of Drug Molecules via Microsolvation Measurements with Differential Mobility Spectrometry

Definitive version is available here: Liu, C., Le Blanc, J. C. Y., Schneider, B. B., Shields, J., Federico, J. J., Zhang, H., … Campbell, J. L. (2017). Assessing Physicochemical Properties of Drug Molecules via Microsolvation Measurements with Differential Mobility Spectrometry. ACS Central Science, 3(2), 101–109. https://doi.org/10.1021/acscentsci.6b00297. This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.http://pubs.acs.org/page/policy/authorchoice_termsofuse.htmlThe microsolvated state of a molecule, represented by its interactions with only a small number of solvent molecules, can play a key role in determining the observable bulk properties of the molecule. This is especially true in cases where strong local hydrogen bonding exists between the molecule and the solvent. One method that can probe the microsolvated states of charged molecules is differential mobility spectrometry (DMS), which rapidly interrogates an ion’s transitions between a solvated and desolvated state in the gas phase (i.e., few solvent molecules present). However, can the results of DMS analyses of a class of molecules reveal information about the bulk physicochemical properties of those species? Our findings presented here show that DMS behaviors correlate strongly with the measured solution phase pKa and pKb values, and cell permeabilities of a set of structurally related drug molecules, even yielding high-resolution discrimination between isomeric forms of these drugs. This is due to DMS’s ability to separate species based upon only subtle (yet predictable) changes in structure: the same subtle changes that can influence isomers’ different bulk properties. Using 2-methylquinolin-8-ol as the core structure, we demonstrate how DMS shows promise for rapidly and sensitively probing the physicochemical properties of molecules, with particular attention paid to drug candidates at the early stage of drug development. This study serves as a foundation upon which future drug molecules of different structural classes could be examined.Natural Sciences and Engineering Research Council of Canada || ENGAGE grant (EGP No. 449354-13) ENGAGE Plus grant || (EGP No.463974-14) Collaborative Research and Development grant || (490885). Ontario Centres of Excellence(OCE) || Voucher for Innovation and Productivity II grant (25050

Theoretical, spectroscopic, and chromatographic study of the structure and properties of para-substituted 5-benzylidenebarbituric acid derivatives with electron-donor and electron-acceptor substituents

5-Benziliden barbiturati pokazuju različitu biološku aktivnost koja je znatno uslovljena fizičkim, hemijskim i strukturnim osobinama jedinjenja, kao i zanimljive optičke osobine koje su posledica donor-akceptorskih interakcija u molekulu. Sintetisana je serija para-supstituisanih derivata 5-benzilidenbarbiturne kiseline kao potencijalnih push-pull elektronskih sistema sa elektron-donorskim i elektron-akceptorskim supstituentima. Proučavane su donor-akceptorske interakcije, kao i potencijalna elektron-donorska sposobnost barbiturne kiseline u sintetisanim jedinjenjima koja do sada nije potvrđena u literaturi. Elektronske interakcije u jedinjenjima u osnovnom stanju proučavane su LFER analizom NMR podataka, zajedno sa analizom optimizovanih geometrija i izračunatih elektronskih gustina. LSER analizom i TD-DFT proračunima proučavane su ekscitacije i pobuđena stanja. Rezultati "hole-electron" analize i izračunatih ICT deskriptora tokom ekscitacije pokazuju da je p-N(CH3)2 derivat najbolji kandidat za push-pull sistem. Utvrđeno je da barbiturna kiselina može biti slab elektron-donor kada je kuplovana sa jakim elektron-akceptorom. Primenom RP TLC metode određeni su hromatografski parametri lipofilnosti sintetisanih jedinjenja u metanolu, n-propanolu, acetonu i tetrahidrofuranu. Ispitana je zavisnost između hromatografskih parametara lipofilnosti (RМ0 i m), softverski dobijenih vrednosti logP kao standardne mere lipofilnosti, farmakokinetičkih i toksikoloških parametara primenom linearne regresije, klasterske analize i analize glavnih komponenata. Retenciono ponašanje ispitivanih jedinjenja znatno je uslovljeno prirodom supstituenata kao i njihovim elektronskim efektima. Rezultati potvrđuju da se hromatografski parametri, RМ0 i m mogu koristiti za opisivanje lipofilnosti ispitivanih jedinjenja.5-Benzylidenebarbiturates show different biological activities that are significantly influenced by the physical, chemical, and structural properties of the compound, as well as interesting optical properties resulting from donor-acceptor interaction in the molecules. A series of para-substituted 5-benzylidenebarbituric acid derivatives as potential push-pull electronic systems with electron-donor and electron-acceptor substituents was synthesized. The potential electron-donor abilities of barbituric acid, which are still not established in the literature, and donor-acceptor interactions in the synthesized compounds were investigated. The electronic interactions in the ground state were investigated by LFER analysis on 13C NMR data together with the analysis of optimized geometries and calculated electron densities. The electron excitations and the nature of excited state were studied by LSER analysis and TDDFT calculations. The results of the “hole-electron” analysis and calculated ICT descriptors during the excitation show that the p-N(CH3)2 derivative is the best candidate for the push-pull system. It has been found that barbituric acid can be a weak electron-donor when coupled with a strong electron-acceptor. The chromatographic lipophilicity parameters of the synthesized compounds were determined by the RP TLC in methanol, n-propanol, acetone, and tetrahydrofuran. The relationship between chromatographic lipophilicity parameters (RМ0 and m), theoretically calculated logP values as a standard measure of lipophilicity, pharmacokinetic and toxicological parameters was examined using the linear regression, cluster analysis, and principal component analysis. The retention behavior of the investigated compounds is significantly conditioned by the nature of the substituents as well as their electronic effects. The results confirm that the chromatographic parameters (RМ0 and m) can be used to describe the lipophilicity of the investigated compounds

Prediction of transformation products during ozonation of micropollutant-containing waters:kinetics and mechanisms

Ozonation, which is widely used for drinking water disinfection, has recently been applied to mitigate potentially harmful effects of micropollutants (e.g., pharmaceuticals, personal care products, pesticides, etc.) present in municipal wastewater effluents. Generally, ozonation is efficient for the abatement of biological effects caused by micropollutants. However, limited empirical information is available about the transformation products formed during ozonation of micropollutants due to analy-tical limitations and a large number of micropollutants present in wastewater effluents. In this thesis, a computer-based prediction platform for kinetics and mechanisms for the reactions of ozone with micropollutants was developed to provide information about (i) the reactivity of micropollutants with ozone expressed as second-order rate constants (kO3, M-1s-1) and (ii) potential transformation products formed from the reactions of ozone with micropollutants. Regarding (i), kO3 for micropollutants were predictable using linear relationships between experimental kO3 in log units for compounds of certain chemical groups (e.g., phenols, olefins, amines, etc.) and the corresponding molecular orbital energies (e.g., highest occupied molecular orbital (HOMO) or natural bond orbital (NBO)) obtained from quantum chemical computations (mostly R2 = 0.75 - 0.95 for 14 compound groups consisting of 284 model compounds in total). Overall, the developed kO3 prediction models could predict kO3 on average within a factor of ~5 of an experimental kO3 for model compounds used for the development of the kO3 prediction models as well as tetrachlorobutadienes, which were externally validated. In contrast, poor kO3 predictions (>10 fold) were observed for some model compounds excluded from the correlations as outliers as well as cetirizine, two pentachlorobutadiene congeners, and hexachlorobutadiene, which were used for external validation. (ii) A prediction tool for potential transformation products was developed based on numerous reaction pathways proposed in literature, which were encoded into 340 individual reaction rules using appropriate chemoinformatics tools. The predicted pathways and the transformation products for some micropollutants (i.e., carbamazepine and tramadol) were shown to be consistent with experimental observations. However, in the future, both kO3 and the pathway prediction modules need to be further validated with more compounds with experimental data and to be improved/updated accordingly. The developed prediction platform is expected to be useful for various groups of end-users in research and practice such as environmental engineers, chemists, or toxicologists. In addition, the treatability of 9 polychlorobutadienes, which are groundwater contaminants, with ozone, UV photolysis at 254nm, and their advanced oxidation processes (i.e., O3/H2O2 and UV/H2O2) was investigated. The abatement efficiencies for poly-chlorobutadienes during ozonation or O3/H2O2 in a natural groundwater could be well explained based on the experimental kO3 and kOH-values. UV treatment was shown to be effective for the abatement of polychlorobutadienes. However, the potential formation of photoisomers from UV irradiation of chlorobutadienes with either E or Z configurations needs to be taken into account because this isomerization will not necessarily lead to a loss of the biological effects of these compounds

Polydentate schiff bases and their Cu(II) complexes: lipophilicity and biological activity.

Šifove baze i njihovi kompleksi pokazuju različitu biološku aktivnost poput antiviralne, antimikrobne, antimalarijske i antikancerske. Zbog činjenice da biološka aktivnost jedinjenja zavisi prvenstveno od lipofilnosti molekula, što je posledica strukture jedinjenja, određivanje i korelacija lipofilnosti sa hemijskom strukturom, kao i određivanje biološke aktivnosti su postali nezaobilazni u sintezi novih lekova...Schiff bases and their complexes are versatile compounds which have various biological activities such as antiviral, antimicrobial, antimalarial, and anticancer activity. Biological activity of compounds depends on their molecular structure, especially lipophilic character. Determination of lipophilicity, its correlation with chemical structure, and biological activity is very important in drug design..

Synthesis and Evaluation of Novel Antifungal Agents Targeting the Fungal Plasma Membrane H+-ATPase

Fungal infections now contribute significantly to microbe-related morbidity and mortality due to there being a limited number of available antifungal agents and limited modes of delivery. Over the past two decades, many pathogenic fungi have developed various modes of resistance to commonly used antifungals. Thus there is a need for novel antifungal agents with novel mechanisms of action. Inhibition of the essential plasma membrane (PM) H+-ATPase of fungi is a potentially effective therapeutic approach in antifungal drug discovery. In order to investigate this, three series (A-C) consisting of a total of thirty-three symmetrical 1,4-diene-3-one (22a-v, 23a-h and 24a-c) compounds have been synthesized. In vitro macro-broth susceptibility testing of 1,4-diene-3-ones showed wide range of inhibition against Saccharomyces cerevisiae (0.2 - 99%) and Candida albicans (0 - 99%). Compounds 22f, 22m, 22n and 22s exhibited highest potency then other compounds from the library against S. cerevisiae (IC50 = 1.21, 2.22, 0.62 and 1.87 μM), however these compounds demonstrated limited activity against C. albicans (IC50 = 114, 525, 474 and 666 μM). In contrast, compounds 23f, 23g and 23h exhibited a higher degree of antifungal activity against C. albicans (IC50 = 68.5, 57.6 and 50.7 μM) and these compounds also showed good potency against S. cerevisiae (IC50 = 8.46, 5.52 and 6.25 μM). To gain an understanding about the mechanism of action of 1,4-diene-3-ones, the H+-ATPase mediated proton pumping by S. cerevisiae was investigated by measuring the pH of the glucose-induced acidification of the external medium. The bis-pyridylidene derivatives of N-methylpiperidin-4-one (23a-c, 60 µM) were determined to be the most potent inhibitors of H+ efflux from S. cerevisiae and the steady state of proton flux from S. cerevisiae was achieved within 10 minutes of medium acidification. A similar result was observed with N-ethylmaleimide (NEM, 60 µM, positive control). Additionally, 23a, 23b and 23c have shown good potency in the macro broth susceptibility assay of S. cerevisiae (IC50 = 12.6, 8.84 and 9.45 µM). Moreover, the most potent compounds 22n and 23h in macro broth susceptibility assay against S. cerevisiae and C. albicans exhibited limited activity to inhibit the proton efflux from S. cerevisiae. To further elucidate the mechanism of action, preliminary structure-activity relationship (SAR) studies was performed. SAR of bis-benzylidene derivatives of N-methylpiperidin-4-one displayed reasonable correlation coefficient (R2 = 0.6746) between the inhibitory activity expressed as log (1/IC50) and an electronic parameter, the 1H-NMR δ-values of proton on the β-carbon. Conversely, SAR of log (1/IC50) and a lipophilic parameter, calculated logP (clogP) of bis-benzylidene derivatives of N-methylpiperidin-4-one showed R2 of 0.4138. This indicates that the inhibitory activity of compounds is due to the influence of electronic property rather than the lipophilic property. In conclusion, the inhibitory action of 1,4-diene-3-ones on yeast suggests a membrane-bound enzyme target for its action. It is hypothesized that these compounds form a covalent C-S thio-ether bond with cysteine residues of proteins of the plasma membrane and eventually inhibit the H+-ATPas

A bioinorganic study of some cobalt(II) Schiff base complexes of variously substituted hydroxybenzaldimines

Syntheses of Schiff bases were carried out by reacting salicylaldyhde, ortho-vanillin, para-vanillin or vanillin with aniline, 1-aminonaphthalene, 4- and 3-aminopyridine, and also with 2- and 3-aminomethylpyridine. The various Schiff bases obtained from the condensation reaction were reacted with CoCl₂.6H₂0, triethylamine stripped CoCl₂.6H₂0 or Co(CH₃COO)₂ to form cobalt(Il) complexes of ratio 2:1. The complexes obtained from cobalt chloride designated as the "A series" are of the general formulae ML₂X₂.nH₂0 , (L = Schiff base, X = chlorine) while those obtained from cobalt acetate or triethylamine stripped cobalt chloride denoted as "B" and C" are of the general formulae ML₂. nH₂0. The few complexes that do not follow the general formulae highlighted above are: IA [M(HL)₃.Cl₂], (L = N-phenylsalicylaldimine), 4A = (MLCl₂), (L = N-phenylvanaldiminato), 7 A and 21 A (ML₂), (L = N-naphthyl-o-vanaldiminato, and N-methy-2-pyridylsalicylaldiminato respectively), 8A = MLCI, (L = N-naphthylvanaldiminato), 12A = M₂L₃Cl₂, (L = N-4-pyridylvanaldiminato), 15A (MLCI), (L = N-3-pyridyl-o-vanaldiminato). The ligands and their complexes were characterized using elemental analyses and cobalt analysis using ICP, FT-IR spectroscopy (mid and far-IR), NIR-UV/vis (diffuse reflectance), UV/vis in an aprotic and a protic solvents, while mass spectrometry, ¹HNMR and ¹³CNMR, was used to further characterized the ligands. The tautomeric nature of the Schiff bases were determined by examining the behaviour of Schiff bases and their complexes in a protic (e.g. MeOH) and non-protic (e.g. DMF) polar solvents. The effects of solvents on the electronic behaviour of the compounds were also examined. Using CDCl₃, the NMR technique was further used to confirm the structures of the Schiff bases. The tentative geometry of the complexes was determined using the spectra information obtained from the far infrared and the diffuse reflectance spectroscopy. With few exceptions, most of the "A" series are tetrahedral or distorted tetrahedral, while the "B + C" are octahedral or pseudooctahedral. A small number of complexes are assigned square-planar geometry owing to the characteristic spectral behaviour shown. In order to determine their biological activity, two biological assay methods (antimicrobial testing and brine shrimp lethality assay) were used. Using disc method, the bacteriostatic and fungicidal activities of the various Schiff bases and their respective complexes to Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa as well as Aspergillus niger, were measured and the average inhibition zones are tabulated and analysed. Both the Schiff bases and their complexes showed varying bacteriostatic and fungicidal activity against the bacteria and fungus tested. The inhibition activity is concentration dependent and potential antibiotic and fungicides are identified. To determine the toxicity of the ligands and their corresponding cobalt(II) complexes, brine shrimp lethality assay was used. The LD₅₀ of the tested compounds were calculated and the results obtained were tabulated for comparison