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Novel 2,4-disulfonylsubstituted 5-aminothiazoles were synthesized and their anticancer activity was assessed at a high dose (10 μM) against NCI 60 cancer cell lines. Compounds 24 and 25 showed the antiproliferative activity with mean growth inhibition about 66.0%. Replacing 4-hydroxypiperidine 24 with the more hydrophilic N-methyl piperazine 25 increased the number of sensitive cell lines while replacing these hydrophilic groups with lipophilic ones abolished the anticancer activity. The COMPARE analysis showed that the tested compounds had a moderate positive correlation with alkylating agents (CCNU and methyl CCNU) and with a purine nucleotide biosynthesis inhibitor analog (L-cysteine). The results indicate that the above mechanisms of antitumor action of standard compounds are not the main ones for the tested compounds due to the lack of a high correlation. The results of this study allow us to consider compounds 24 and 25 as a basis for their further functionalization to obtain more active compounds.

On the base of 3-formylpicolinic acid by two successive heterocyclizations (the formation of a pyrone fragment by the cyclization of chloroacetone with the carboxyl and formyl groups; and the construction of the thiazole cycle through the bromination of the acetyl fragment and following interaction with thioamides), 6-(2-(phenyl/thiophen-2-yl)thiazole-4-yl)-8H-pyrano[3,4-b]pyridin-8-ones were obtained; and then the pyrone fragment was converted to pyridone by the action of ammonia under high pressure. When such 6-(2-R-thiazol-4-yl)-1,7-naphthyridin-8(7H)-ones reacted with triflic anhydride, O-sulfonylation of the pyridone fragment occurred, after that triflate group was easily substituted by secondary cyclic aliphatic amines. Thus, a number of new 8-amino-6-(2-R-thiazol-4-yl)-1,7-naphthyridines – previously inaccessible heterocyclic derivatives with promising biological activity – were obtained.

Here we describe the results of QSAR analysis based on artificial neural networks, synthesis, activity evaluation and molecular docking of a number of 1,3-oxazole derivatives as anti-E. coli antibacterials. All developed QSAR models showed excellent statistics on training (with determination coefficient q2 as 0.76 ± 0.01) and test samples (with q2 as 0.78 ± 0.01). The models were successfully used to identify nine novel 5-amino-4-cyano-1,3-oxazoles with potential anti-E. coli activity. All nine 1,3-oxazoles with predicted high antibacterial potential showed different levels of anti- E. coli in vitro activity. 5-amino-4-cyano-1,3-oxazoles 1 and 3 showed the highest antibacterial activity on average from 17 to 27 mm against MDR, hemolytic MDR and ATCC 25922 E. coli colistin-resistant strains, respectively. The comparative docking analysis demonstrated a possible mechanism of the antibacterial action of the studied 1, 3-oxazoles 1 and 3 through inhibition of E. coli enoyl-ACP reductase (ENR) involved in the biosynthesis of bacterial fatty acids. The localization type is shown of 5-amino-4-cyano-1,3-oxazoles 1 and 3 into the E. coli ENR active site with estimated binding energy from − 10.1 to − 9.5 kcal/mol and hydrogen bonds formation with key amino acids similar to Triclosan. These facts confirm the validity of the hypothesis put forward about the potential antibacterial mechanism of 5-amino-4- cyano-1,3-oxazoles.

O-Acyl substituted derivatives of 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium chloride which is a structural analog of vitamin B1 were synthesized and evaluated towards acetylcholinesterase and butyrylcholinesterase in vitro. The inhibition properties of the O-substituted compounds depend on nature of substituents at position 3 and 5 of the thiazolium ring. Some of the thiazolium salts showed high potency in the inhibition of only one of the two enzymes. The selective effects of these inhibitors are governed by substituent at position 5. Kinetic studies and molecular docking simulation were performed for elucidating mechanisms of enzyme-inhibitor complex formation.

Five imidazo[1,2-c]pyrimidine and pyrimido[1,6-a]pyrimidine derivatives were designed, synthesized and evaluated for their antiproliferative activity and cytotoxicity. Primary bioassays in vitro showed that two of five synthesized compounds, 6-benzyl-8-(methylsulfonyl)-2,6-dihydroimidazo[1,2-c]pyrimidin-5(3H)-one, and 9-(methylsulfonyl)-7-propyl-2,3,4,7-tetrahydro-6H-pyrimido[1,6-a]pyrimidin-6-one possessed potent antiviral activity against BKV (EC50: 0.66 μM and 0.96, respectively). The selectivity index of these compounds is similar to that of cidofovir. Although antiviral activity was evident in secondary assays, significant virus inhibition occurred at or near the cytotoxic concentration (SI90=1). Here we show that substituted pyrimidine derivatives are a promising structure class of chemical compounds for the development of antiviral drugs against BKV infections. Hence these compounds may be taken as lead compounds for further development of novel antimicrobial and anticancer agents.

A series of benzenesulfonamides incorporating pyrazole- and pyridazinecarboxamides decorated with several bulky moieties has been obtained by original procedures. The new derivatives were investigated for the inhibition of four physiologically crucial human carbonic anhydrase (hCA, EC 4.2.2.1.1) isoforms, hCA I and II (cytosolic enzymes) as well as hCA IX and XII (transmembrane, tumor-associated isoforms). Examples of isoform-selective inhibitors were obtained for all four enzymes investigated here, and a computational approach was employed for explaining the observed selectivity, which may be useful in drug design approaches for obtaining inhibitors with pharmacological applications useful as antiglaucoma, diuretic, antitumor or anti-cerebral ischemia drugs.

Carbonic Anhydrases (CAs) are ubiquitous metalloenzymes involved in several disease conditions. There are 15 human CA (hCA) isoforms and their high homology represents a challenge for the discovery of potential drugs devoid of off-target side effects. For this reason, many synthetic and pharmacologic research efforts are underway to achieve the full pharmacological potential of CA modulators of activity. We report here a novel series of sulfanilamide derivatives containing heterocyclic carboxamide moieties which were evaluated as CA inhibitors against the physiological relevant isoforms hCA I, II, IX, and XII. Some of them showed selectivity toward isoform hCA II and hCA XII. Molecular docking was performed for some of these compounds on isoforms hCA II and XII to understand the possible interaction with the active site amino acid residues, which rationalized the reported inhibitory activity.

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho/physiological conditions. A series of chromene-based sulfonamides were synthesized and tested as possible CA inhibitors. Their inhibitory activity was assessed against the cytosolic human isoforms hCA I, hCA II and the transmembrane hCA IX and XII. Several of the investigated derivatives showed interesting inhibition activity towards the tumor associate isoforms hCA IX and hCA XII. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds, within the active site of hCA IX.