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The quantitative structure–activity relationship (QSAR) methodology was used to predict the blood–brain permeability (log BB) for 65 synthetic heterocyclic compounds tested as promising drug candidates. The compounds were characterized by different descriptors: lipophilicity, parachor, polarizability, molecular weight, number of hydrogen bond acceptors, number of rotatable bonds, and polar surface area. Lipophilic properties of the compounds were evaluated experimentally by micellar liquid chromatography (MLC). In the experiments, sodium dodecyl sulfate (SDS) as the effluent component and the ODS-2 column were used. Using multiple linear regression and leave-one-out cross-validation, we derived the statistically significant and highly predictive quantitative structure–activity relationship models. Thus, this study provides valuable information on the expected properties of the substances that can be used as a support tool in the design of new therapeutic agents. [ABSTRACT FROM AUTHOR]

The goals of the present investigation were the development of two independent synthetic approaches, the original spectroscopic characterisation, the identification of in vitro antitumour activities and the correlation of determined retention factors with in silico pharmacokinetic descriptors of two novel classes of potential antimetabolites based on the privileged 7,8-dihydroimidazo[2,1- c ][1,2,4]triazin-4(6 H)-one scaffold. Well-established, scalable and optimised synthetic approaches leading to two novel classes of the desired compounds (7–12 and 13–17) were developed. These original fused azaisocytosine-like congeners were screened in vitro with the purpose of identifying molecules with better biological profiles that are suitable for further more detailed drug development studies. All the synthesised compounds proved to be strongly antiproliferative active against human neoplastic cell lines (A549, HeLa, T47D and TOV112D) and revealed higher cytotoxic effects in A549, HeLa and T47D cells than the known antitumour agent – pemetrexed. Four potent fused azaisocytosine-like congeners (10 , 12 , 15 and 16) proved to be the most promising lead structures as they reveal the explicitly lower cytotoxicity for non-tumoural cells. These molecules could be employed for novel effective anticancer strategies directed towards designing more selective and safer cytotoxic agents. In addition, a number of compounds (that target epithelial cancer cells and inhibit their growth) have been preselected because they present optimum lipophilicity ranges significantly correlated with in silico bioactivity descriptors (such as % F , Caco-2, P e,jejunum , log BB, f u,brain , log P HSA) important for the optimal pharmacokinetic profile in vivo. [ABSTRACT FROM AUTHOR]

Abstract: Eleven novel 3-(2-furanyl)-8-aryl-7,8-dihydroimidazo[2,1-c][1,2,4]triazin-4(6H)-ones (12–22) were designed and obtained from appropriate 1-aryl-2-hydrazonoimidazolidines (1–11) by condensation reaction with 2-oxo-2-furanacetic acid and subsequent cyclocondensation of intermediate chain derivatives. IR, 1H NMR and 13C NMR spectra and elemental analyses confirmed the chemical structure of all the synthesized compounds. The reversed-phase HPLC method was optimized and proved to be applicable and reliable for the analysis of these unknown small molecules (12–22). These compounds were chromatographed on octadecyl silica (ODS) stationary phase and their hydrophobic parameters expressed as the log k w values were determined by RP-HPLC, using mixtures of methanol and water as mobile phases with different methanol concentrations. Octane-1-sulfonic acid sodium salt (OSA-Na) and 20% acetate buffer (pH 3.5) was added to the mobile phase (eluent containing 0.01M/L OSA-Na in organic modifier (MeOH)—buffered mobile phase). The high values of regression coefficients (r >0.9841) for all the compounds investigated proved the excellent fit between experimental data and the Snyder–Soczewiński equation. Results obtained from the reversed-phase HPLC were compared both with those theoretically calculated and with those obtained from an ALOGPS 2.1. software by the use of nine different computational methods for estimation of log P. The predicted values of log P by use of AB log P algorithm revealed the best correlation with the experimental log k w values for the investigated solutes, since a good correlation (r =0.7760) between these quantities was found. The majority of novel imidazotriazinones were found to be evidently effective in vitro against human cancerous cells (HeLa and T47D) in an effective concentration of 50μg/mL. Five compounds (13, 15, 16, 18 and 22) revealed remarkable antiproliferative activities and selective cytotoxicities for cancer cells over normal HSF cells. Therefore these ones may be considered as a basis for the design of novel useful non-toxic (13, 15 and 16) and low toxic (18 and 22) anticancer agents. [Copyright &y& Elsevier]

Abstract: Eight novel antitumour and analgesic active 8-aryl-2,6,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazine-3,4-diones (1–8) have been obtained as a bioactive set of substances and their lipophilicity has been studied. The log k values of fifteen reference compounds and eight newly synthesised imidazotriazine-3,4-dione derivatives were determined by reversed-phase high performance liquid chromatography (RP-HPLC) using mixtures of methanol and water as mobile phases with different methanol concentrations. The relationships between log k values of a set of reference compounds (fifteen compounds) and investigated ones (eight compounds) and concentration of methanol was used for determination of the log k water values by extrapolation. The partition coefficients (log P) values for reference compounds measured experimentally were taken from the literature. The calibration equation was then obtained for the standards of known lipophilicity (log P HPLC) and log k water. In next step the partition coefficients of new synthesised solutes were calculated from the calibration equation. For the comparison purpose, additionally the partition coefficients (log P calc.) of the examined imidazotriazine-3,4-diones were calculated by means of the Pallas 3.1.1.2. software. It was found that log k water values as a lipophilicity measure of derivatives correlate well with partition coefficients measured experimentally (log P HPLC). Correlation between the log P HPLC and the logarithm of partition coefficient calculated by Pallas software (log P calc.) is not so satisfactory as that for values determined experimentally. Furthermore, it has been found that the lipophilicity variation of investigated imidazotriazine-3,4-diones (1–8) correlates well with their acute toxicity expressed as log(1/LD50). The drug-likeness of all the bioactive 8-aryl-2,6,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazine-3,4-diones was assessed on the basis of their structural properties by applying Lipniski''s rule of five. The solutes have all four parameters important for the favourable pharmacokinetics in the human body that would make them likely orally active drugs in humans. [Copyright &y& Elsevier]

Abstract: 3-Unsubstituted and 3-substituted-7-aryl-5H-6,7-dihydroimidazo[2,1-c][1,2,4]triazoles (1–14) were designed and obtained from biologically active 1-aryl-2-hydrazonoimidazolidines by cyclocondensation reaction with triethyl orthoformates (1–4), phenoxyacetic acid derivatives (5–13) and carbon disulfide (14), respectively. Their chemical structures were confirmed by IR, 1H NMR, 13C NMR, MS spectra and elemental analysis. In the high performance liquid chromatographic series of experiments, fourteen synthesized compounds (1–14) were chromatographed on octadecyl silica adsorbent and their lipophilicity parameter (log k W) was determined using various aqueous systems: mixture of water and organic modifiers (methanol – MeOH, acetonitrile – MeCN or dioxane – DX). Compounds 7 and 12 were evaluated for their cytotoxic activity against three cancer cell lines: human Caucasian colon adenocarcinoma cell line – LS180 (ECACC 87021202), human uterus carcinoma cell line – SiHa (ECACC 85060701) and human breast carcinoma cell line – T47D (ECACC 85102201). Compound 12 was found to be the most effective in vitro against human colon adenocarcinoma cell line (LS180). Moreover, the distinctly marked lower cytotoxicity of compounds 7 and 12 against the normal cell line – human skin fibroblasts (HSF) and almost several-fold higher against the examined cancer cell lines was ascertained. The cytotoxic effect of imidazotriazole 7 was noticed on DNA structure of breast cancer cell line (T47D) by using the comet assay. Compound 7 in concentration of 29.3μM was found to possess efficiency for DNA strand breakage. In particular, this led to cutting of the DNA strands and formation of small fragments of DNA – two higher and one lighter in comparison with control DNA. Moreover, significant viability decreases in the human leukaemic RPMI 8226 cells treated with different concentrations of imidazotriazoles 8–12 were observed, suggesting their antiproliferative properties. Besides, three tested compounds (9, 13, 14) revealed significant antimicrobial activities with MIC values in the range of 30.9–44.0μM. Compound 13 showed superior antibacterial activity to ampicillin and chloramphenicol in vitro, whereas 14 displayed superior antifungal activity to miconazole. [Copyright &y& Elsevier]

Highlights: [•] Parabolic relationships between biological and log k w values were obtained. [•] Extrapolated retention parameters were used as lipophilicity descriptors. [•] Cholesterol column is excellent to predict lipophilicity and bioactivity. [Copyright &y& Elsevier]

The chromatographic behaviour and significant lipophilicity/hydrophobicity indices (log k w , S , φ 0 ) are presented for 21 biologically active fused 1,2,4-triazinones based on the linear relationship: log k = log k w − Sφ established for the retention on LC-18 HPLC column, using as mobile phases mixtures of three organic modifiers with water. The effect of these mobile phase modifiers on the chromatographic behaviour of solutes was established and the organic modifier of choice is suggested. The complex correlation of slopes versus intercepts obtained for acetonitrile, contrary to linear ones obtained for methanol and dioxane are disclosed. The observed difference in retention mechanism for acetonitrile compared to methanol and dioxane is explained by intermolecular interactions encoded in lipophilicity. Linear correlations with statistically significant levels between log k w values determined from three different chromatographic systems were obtained. The relationships between log k w constants (derived from the linear model for methanol–water mobile phases) and predicted log P and log S values by the use of various computational methods were investigated and these were established with high correlation coefficients. The predicted log P values plotted against φ 0 (MeOH) indices showed the best fit. Principal component analysis was used to compare various lipophilicity parameters of the solutes and their in silico biological descriptors relevant to optimal pharmacokinetics profile. The similarities and dissimilarities between all the variables and molecular structures of solutes are presented. Statistically significant correlations were found between the chromatographic lipophilicity indices and the calculated pharmacokinetic descriptors: fraction unbound in brain ( f u, brain ), oral bioavailability (%F), permeability and intestinal absorption in jejunum (Caco-2), skin permeation (log K p ) and blood/brain concentration (log BB). [ABSTRACT FROM AUTHOR]