This work describes the multigram-scale synthesis of the building-block N1 (7 chloroquinolin-4-yl)ethane-1,2-diamine via sonochemistry and its use in the synthesis of seven new quinoline-thiazole hybrids endowed with interesting anticancer activity. Target compounds were planned based on the drugs chloroquine and primaquine and the desired thiazoles were obtained through the Hantzsch thiazole synthesis, without the use of catalysts, by reacting key intermediate 1-(2-((7-chloroquinolin-4-yl)amino)ethyl)thiourea, obtained in two-steps from N1 (7-chloroquinolin-4-yl)ethane-1,2-diamine, with different 2-bromoacetophenones. The novel molecules were assessed against four different leukemia cell lines (HL60, K562, KASUMI-1, and KG-1) plus normal fibroblasts (L929), using the 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, and showed, overall, a high cytotoxic profile, but with interesting selectivity index, especially against K562 cells (1.89 to 5.50), when compared to standard doxorubicin (3.51). Docking studies suggest that all tested derivatives are able to interact with BCR-ABL1 tyrosine kinase enzyme, and, therefore, these molecules may be promising leads against chronic myeloid leukemia. multigramscale multigram scale buildingblock building block N 7 ( chloroquinolin4ylethane1,2diamine chloroquinolin4ylethane12diamine chloroquinolinylethanediamine chloroquinolin 4 yl ethane 1,2 diamine 1 2 quinolinethiazole quinoline activity catalysts 127chloroquinolin4ylaminoethylthiourea, 127chloroquinolin4ylaminoethylthiourea chloroquinolinylaminoethylthiourea amino ethyl thiourea, thiourea 1-(2-((7-chloroquinolin-4-yl)amino)ethyl)thiourea twosteps two steps 7chloroquinolin4ylethane1,2diamine, 7chloroquinolin4ylethane12diamine diamine, (7-chloroquinolin-4-yl)ethane-1,2-diamine 2bromoacetophenones. 2bromoacetophenones bromoacetophenones bromoacetophenones. 2-bromoacetophenones HL60, HL60 HL (HL60 K KASUMI1, KASUMI1 KASUMI 1, KASUMI-1 KG1 KG KG-1 L929, L929 L , (L929) 34,5dimethyl2thiazol2,5diphenyl2Htetrazolium 345dimethyl2thiazol25diphenyl2Htetrazolium dimethylthiazoldiphenylHtetrazolium 3 4,5 dimethyl thiazol 2,5 diphenyl 2H tetrazolium 5 H MTT (MTT assay showed overall profile index K56 1.89 189 89 (1.8 5.50, 550 5.50 50 5.50) 3.51. 351 3.51 . 51 (3.51) BCRABL1 BCRABL BCR ABL1 ABL BCR-ABL enzyme therefore chloroquinolin4ylethane1 2diamine ylethane 12 ylaminoethylthiourea 7chloroquinolin4ylethane1 7chloroquinolin4ylethane1,2diamine HL6 (HL6 KASUMI- KG- L92 (L929 34 5dimethyl2thiazol2 5diphenyl2Htetrazolium Htetrazolium 45 4, 25 2, K5 1.8 18 8 (1. 55 5.5 35 3.5 (3.51 chloroquinolinylethane chloroquinolin4ylethane 7chloroquinolin4ylethane (HL L9 (L92 dimethylthiazol 5dimethyl2thiazol diphenylHtetrazolium 1. (1 5. 3. (3.5 (L9 (3. (L (3

Humankind has experienced a remarkable development since it began to design and optimize chemical reactions to achieve valuable compounds. The key to accomplish these tasks is the proper understanding of how chemical transformations occur at a molecular level, that is, their reaction mechanisms. Based on a suitable mechanistic proposal, experimentalists choose a given chemical protocol to optimize experimental conditions, design new synthetic routes, and circumvent competing reactions. In this context, computational chemistry has become a valuable ally for mechanistic elucidation. We present herein a review of complementary collaborations between experimentalists and theoretical chemists to rationalize processes at the molecular level, focusing mainly on the fields of organic synthesis, natural product chemistry, and systems with environmental interest. Throughout this review, we highlight the ability of computational evaluations to provide answers to questions raised from experiments in a clear and direct way, indicating to experimentalists alternative paths to help them solve their problems. compounds level mechanisms proposal conditions routes context elucidation synthesis interest way problems

This work describes the first determination of the absolute configuration (AC) of (−)-cubebin by means of electronic circular dichroism (ECD), supported by quantum chemical calculations. The comparison of experimental ECD with the corresponding quantum chemical prediction for the proper diastereoisomer resulted in the definitive assignment of the AC of the naturally occurring (−)-cubebin as (8R,8aR,9S). The challenging determination of the relative configuration (RC) of cubebin based only on experimental nuclear magnetic resonance (NMR) methods is stressed. Computation of the 13C and 1H NMR chemical shifts for all the possible diastereoisomers leads to values of mean absolute error and root mean square deviation that do not allow distinguishing among them. Thus, errors in stereochemical determination can easily occur even when using two-dimensional methods, which clearly demonstrate the complexity of this special case. To determine the RC of this bioactive natural compound with high level of confidence, it was necessary to combine the DP4+ method with X-ray crystallography. Therefore, employing the commonly used empirical methods to determine the AC of (−)-cubebin can easily lead to misassignment of its stereochemistry.

Three molecular hybrids containing 1,4-naphthoquinones, 1,3,5-triazines, morpholine and 7-chloroquinoline, which have recognized contributions to the biological activity of many drugs, were synthesized in yields ranging from 43-84%. All hybrids were obtained in three steps starting from readily available reactants: lawsone, cyanuric chloride, morpholine and 4,7-dichloroquinoline. A previous docking study was carried out to identify the binding energy and pharmacophore conformation of the promising anticancer compounds with PI3Kγ (phosphoinositide 3-kinase) and AMPK (5’ AMP-activated protein kinase). The cancer activity in human metastatic melanoma cells (SKMEL-103) were performed, and the synthetized compounds presented half maximal inhibitory concentration (IC50) values around 25 µM. The expressions of PI3K and AMPK were also determined using western blotting technique, and all molecular hybrids negatively modulated both targets.

Density functional theory calculations (ωB97X-D/6-311++G(d,p)) are employed to investigate an alternative pathway for Prins-like cyclization. Although strong acids usually catalyze this reaction, 4-amino-1,3-dioxanes are rapidly obtained in high yields without catalyst when benzenamines and acetaldehyde react at low temperatures, in aqueous medium. Considering these conditions, we applied a supermolecule model with explicit water molecules to compute the mechanism for 4-amino-1,3-dioxanes formation from the reactants. The structure of the primary solvation shell was determined by Metropolis Monte Carlo method. In the Prins-cyclization step, we found an unpredicted pathway with non-ionic transition structures or intermediates. Explicit water molecules establish a net of hydrogen bonds allowing prototropism, maintaining the electrical neutrality in the system while two protons transfer occurs. To provide data to further experimental confirmation of this hypothesis, we estimated the kinetic isotope effect for the reaction. We also investigated the use of aliphatic amines, which indicates that the reaction may be of a broader application than first observed experimentally.

Hydroxynaphthoquinones such as lawsone (2-hydroxy-1,4-naphthoquinone) have proven to be effective antifungal agents. These compounds were tested for antifungal activity against yeast standard and clinical strains by the broth microdilution method. Among the synthetic lawsone derivatives, 2-hydroxy-3-((2-hydroxyphenyl)(pyrrolidin-1-yl)methyl)naphthalene-1,4-dione, 2-hydroxy-3-(((4-nitrophenyl)amino)(phenyl)methyl)naphthalene-1,4-dione and 2-hydroxy-3-((2-hydroxyphenyl)((4-nitrophenyl)amino)methyl)naphthalene-1,4-dione showed high activity against Candida albicans ATCC 10231, with minimal inhibitory concentrations (MICs) and minimal fungicidal concentrations (MFCs) ranging from 20 to 330 and from 80 to 330 µg mL-1, respectively. Moreover, they also showed a mechanism of action on exogenous ergosterol. Therapeutic concentrations (CC50) of 2-hydroxy-3-((2-hydroxyphenyl)(pyrrolidin-1-yl)methyl)naphthalene-1,4-dione, 2-hydroxy-3-(((4-nitrophenyl)amino)(phenyl)methyl)naphthalene-1,4-dione and 2-hydroxy-3-((2-hydroxyphenyl)((4-nitrophenyl)amino)methyl)naphthalene-1,4-dione were 52.81, 52.58 and 85.94 µg mL-1, respectively, which can be considered moderate or low. In addition, docking studies showed that these compounds had similar binding energy to standard ketoconazole, which are recognized as the molecular target by van der Waals interactions. Furthermore, they are under Lipinski's rule of 5 with a druglikeness score better than ketoconazole and nystatin. These findings suggest that 2-hydroxy-3-((2-hydroxyphenyl)(pyrrolidin-1-yl)methyl)naphthalene-1,4-dione, 2-hydroxy-3-(((4-nitrophenyl)amino)(phenyl)methyl)naphthalene-1,4-dione and 2-hydroxy-3-((2-hydroxyphenyl)((4-nitrophenyl)amino)methyl)naphthalene-1,4-dione have potential as leading compounds against human fungal infections.