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Docking analysis was used to predict the effectiveness of adamantanyl insertion in improving cycloxygenase/lipoxygenase (COX/LOX) inhibitory action of previously tested 2-thiazolylimino-5-arylidene-4-thiazolidinones. The crystal structure data of human 5-LOX (3O8Y), ovine COX-1 (1EQH) and mouse COX-2 (3ln1) were used for docking analysis. All docking calculations were carried out using AutoDock 4.2 software. Following prediction results, 11 adamantanyl derivatives were synthesized and evaluated for biological action. Prediction evaluations correlated well with experimental biological results. Comparison of the novel adamantanyl derivatives with the 2-thiazolylimino-5-arylidene-4-thiazolidinones previously tested showed that insertion of the adamantanyl group led to the production of more potent COX-1 inhibitors, as well as LOX inhibitors (increased activity from 200% to 560%). Five compounds out of the 11 exhibited better activity than naproxen; while nine out of 11 showed better activity than NDGA and seven compounds possessed better anti-inflammatory activity than indomethacin.

A new thiazole-containing multidentate ligand 2-((2-phenylthiazol-4-yl)methylthio)ethanamine, L, was synthesized and used to prepare new complexes of the formula PdIILCl2 (Pd–L), CuIIL2Cl2 (Cu–L) and fac-[Re/99mTcI(CO)3(L)]+ (Re/99mTc–L). The ligand L and the metal complexes were characterized spectroscopically. Furthermore, the structures of Re–L and Cu–L were elucidated by X-ray crystallography. Ligand L acts as a bidentate (Nth, S) chelator in Pd–L, as a bidentate (N, S) chelator in Cu–L and as a tridentate (Nth, S, N) chelator in Re–L. The radiotracer 99mTc–L was synthesized in high yield and characterised by HPLC comparison with the Re–L analog. The synthesized compounds were evaluated for their anti-inflammatory and cytotoxic properties. The compounds exhibited low anti-inflammatory activity with Pd–L showing the highest activity among them. The cytotoxic activity of the ligand and the complexes against several human cancer cell lines (cervical adenocarcinoma HeLa, colorectal adenocarcinoma LS-174T, lung adenocarcinoma A549, breast adenocarcinoma MDA-MB-231 and normal human lung fibroblast cell line MRC-5) was examined using the MTT assay. The complex Cu–L exhibited the highest cytotoxicity and the complex Pd–L showed the best tumor selectivity. The changes in the cell cycle phase distribution were determined by flow cytometry and it was found that ligand L shows the highest apoptotic activity. The biodistribution studies of 99mTc–L in mice showed fast tissue clearance. Of all the thiazole-containing compounds, the palladium complex appears to be more promising for future efforts.

We report herein, two synthetic approaches to three types of nitrogen-containing bisphosphonates (N-BPs) in moderate to high yields (58–88%). Ester cleavage of selected bisphosphonates was undertaken to obtain their N-BP-acid analogs. Based on the reported bisphosphonate properties and the prospective biological prediction using computer-assisted molecular modeling (CAMM), new compounds were evaluated in a mouse model of antigen-induced arthritis (AIA) and the delayed-type hypersensitivity granuloma reaction (DTH-GRA) for chronic inflammation. Pharmacological results showed that N-BP-acids are more favorable for antiarthritis activity than N-BP-esters. On the other hand, the majority of N-BPs revealed good antiinflammatory potency compared to their acid analogs. The results also showed that the presence of a free thiol group in a molecule enhances the anti-inflammatory activity. Furthermore, bioscreening results were in good agreement with the prediction investigation. A hypothesis of molecular modeling study, including fitting of the synthesized compounds into 3D-pharmacophore using Discovery Studio 2.5 software and their docking into the human farnesyl pyrophosphate synthase (hFPPS, PDB code: 2F8C protein) showed good results consistent with the observed pharmacological properties.

Background: From the literature it is known that many derivatives of fused thienopyrimidines and furopyrimidines possess broad spectrum of biological activity. Objectives: The current studies describe the synthesis and evaluation of antimicrobial activity of some new N-1,3-thiazol-2-ylacetamides of pyrido[3',2':4,5]furo(thieno)[3,2-d]pyrimidines. Methods: By cyclocondensation of ethyl 1-aminofuro(thieno)[2,3-b]pyridine-2-carboxylates 1with formamide were converted to the pyrido[3',2':4,5]furo(thieno)[3,2-d]pyrimidin-7(8)-ones 2.Alkylation of compound 2 with 2-chloro-N-1,3-thiazol-2-ylacetamide led to the aimed N-1,3-thiazol-2-ylaceta-mides of pyrido[3',2':4,5]furo(thieno)[3,2-d]pyrimidines 3. Starting from compound 2 the relevant S-alkylated derivatives of pyrido[3',2':4,5]furo(thieno)[3,2-d]pyrimidines 6 were also synthesized. Results: All the compounds showed antibacterial activity to non-resistant strains. Compounds 3a-3m showed antibacterial activity with MIC/MBC at 0.08-2.31 mg/mL/0.11-3.75 mg/mL .The two most active compounds, 3j and 6b, appeared to be more active towards MRSA than the reference drugs. Half of the tested compounds appeared to be equipotent/more potent than ketoconazole and more potent than bifonazole. The docking analysis provided useful information about the interactions occurring between the tested compounds and the different enzymes. Conclusion: Gram-negative and Gram-positive bacteria and fungi showed different response towards tested compounds, indicating that different substituents may lead to different modes of action or that the metabolism of some bacteria/fungi was better able to overcome the effect of the compounds or adapt to it.

Background: Although a great number of the targets of antimicrobial therapy have been achieved, it remains among the first fields of pharmaceutical research, mainly because of the development of resistant strains. Docking analysis may be an important tool in the research for the development of more effective agents against specific drug targets or multi-target agents 1-3. Methods: In the present study, based on docking analysis, ten tetrahydrothiazolo[2,3-a]isoindole derivatives were chosen for the evaluation of the antimicrobial activity. Results: All compounds showed antibacterial activity against eight Gram-positive and Gram-negative bacterial species being, in some cases, more potent than ampicillin and streptomycin against all species. The most sensitive bacteria appeared to be S. aureus and En. Cloacae, while M. flavus, E. coli and P. aeruginosa were the most resistant ones. The compounds were also tested for their antifungal activity against eight fungal species. All compounds exhibited good antifungal activity better than reference drugs bifonazole (1.4 – 41 folds) and ketoconazole (1.1 – 406 folds) against all fungal species. In order to elucidate the mechanism of action, docking studies on different antimicrobial targets were performed. Conclusion: According to docking analysis, the antifungal activity can be explained by the inhibition of the CYP51 enzyme for most compounds with a better correlation of the results obtained for the P.v.c. strain (linear regression between estimated binding Energy and log(1/MIC) with R 2 =0.867 and p=0.000091 or R 2 = 0.924, p= 0.000036, when compound 3 is excluded.

1,2,4-Triazole is a very important scaffold in medicinal chemistry due to the wide spectrum of biological activities and mainly antifungal activity of 1,2,4-triazole derivatives. The main mechanism of antifungal action of the latter is inhibition of 14-alpha-demethylase enzyme (CYP51). The current study presents synthesis and evaluation of eight triazole derivatives for their antimicrobial activity. Docking studies to elucidate the mechanism of action were also performed. The designed compounds were synthesized using classical methods of organic synthesis. The in vivo evaluation of antimicrobial activity was performed by microdilution method. All tested compounds showed good antibacterial activity with MIC and MBC values ranging from 0.0002 to 0.0069 mM. Compound 2 h appeared to be the most active among all tested with MIC at 0.0002–0.0033 mM and MBC at 0.0004–0.0033 mM followed by compounds 2f and 2g. The most sensitive bacterium appeared to be Xanthomonas campestris while Erwinia amylovora was the most resistant. The evaluation of antifungal activity revealed that all compounds showed good antifungal activity with MIC values ranging from 0.02 mM to 0.52 mM and MFC from 0.03 mM to 0.52 mM better than reference drugs ketoconazole (MIC and MFC values at 0.28–1.88 mM and 0.38 mM to 2.82 mM respectively) and bifonazole (MIC and MFC values at 0.32–0.64 mM and 0.64–0.81 mM). The best antifungal activity is displayed by compound 2 h with MIC at 0.02–0.04 mM and MFC at 0.03–0.06 mM while compound 2a showed the lowest activity. The results showed that these compounds could be lead compounds in search for new potent antimicrobial agents. Docking studies confirmed experimental results.

Background:Bacterial infections are a growing problem worldwide causing morbidity and mortality mainly in developing countries. Moreover, the increased number of microorganisms, developing multiple resistances to known drugs, due to abuse of antibiotics, is another serious problem. This problem becomes more serious for immunocompromised patients and those who are often disposed to opportunistic fungal infections.Objective:The objective of this manuscript is to give an overview of new findings in the field of antimicrobial agents among five-membered heterocyclic compounds. These heterocyclic compounds especially five-membered attracted the interest of the scientific community not only for their occurrence in nature but also due to their wide range of biological activities.Method:To reach our goal, a literature survey that covers the last decade was performed.Results:As a result, recent data on the biological activity of thiazole, thiazolidinone, benzothiazole and thiadiazole derivatives are mentioned.Conclusion:It should be mentioned that despite the progress in the development of new antimicrobial agents, there is still room for new findings. Thus, research still continues.

Griseofulvin is a well-known antifungal drug that was launched in 1962 by Merck & Co. for the treatment of dermatophyte infections. However, according to predictions using the Way2Drug computational drug repurposing platform, it may also have antibacterial activity. As no confirmation of this prediction was found in the published literature, this study estimated in-silico antibacterial activity for 42 griseofulvin derivatives. Antibacterial activity was predicted for 33 of the 42 compounds, which led to the conclusion that this activity might be considered as typical for this chemical series. Therefore, experimental testing of antibacterial activity was performed on a panel of Gram-positive and Gram-negative micro-organisms. Antibacterial activity was evaluated using the microdilution method detecting the minimal inhibitory concentration (MIC) and the minimal bactericidal concentration (MBC). The tested compounds exhibited potent antibacterial activity against all the studied bacteria, with MIC and MBC values ranging from 0.0037 to 0.04 mg/mL and from 0.01 to 0.16 mg/mL, respectively. Activity was 2.5-12 times greater than that of ampicillin and 2-8 times greater than that of streptomycin, which were used as the reference drugs. Similarity analysis for all 42 compounds with the (approximately) 470,000 drug-like compounds indexed in the Clarivate Analytics Integrity database confirmed the significant novelty of the antibacterial activity for the compounds from this chemical class. Therefore, this study demonstrated that by using computer-aided prediction of biological activity spectra for a particular chemical series, it is possible to identify typical biological activities which may be used for discovery of new applications (e.g. drug repurposing).

Background: HIV is the causative agent of Acquired Immunodeficiency Syndrome (AIDS), an infectious disease with increasing incidence worldwide. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) play an important role in the treatment of AIDS. Although, many compounds are already being used as anti-HIV drugs, research for the development of new inhibitors continues as the virus develops resistant strains. Methods: The best features of available NNRTIs were taken into account for the design of novel inhibitors. PASS (Prediction of activity spectra for substances) prediction program and molecular docking studies for the selection of designed compounds were used for the synthesis. Compounds were synthesized using conventional and microwave irradiation methods and HIV RT inhibitory action was evaluated by colorimetric photometric immunoassay. Results: The evaluation of HIV-1 RT inhibitory activity revealed that seven compounds have significantly lower &Iota, C50 values than nevirapine (0.3 &mu, &Mu, ). It was observed that the activity of compounds depends not only on the nature of substituent and it position in benzothiazole ring but also on the nature and position of substituents in benzene ring. Conclusion: Twenty four of the tested compounds exhibited inhibitory action lower than 4 &mu, Seven of them showed better activity than nevirapine, while three of the compounds exhibited IC50 values lower than 5 nM. Two compounds 9 and 10 exhibited very good inhibitory activity with IC50 1 nM.

Infections caused by Fasciola species are widely distributed in cattle and sheep causing significant economic losses, and are emerging as human zoonosis with increasing reports of human cases, especially in children in endemic areas. The current treatment is chemotherapeutic, triclabendazole being the drug of preference since it is active against all parasite stages. Due to the emergence of resistance in several countries, the discovery of new chemical entities with fasciolicidal activity is urgently needed. In our continuous search for new fasciolicide compounds, we identified and characterized six quinoxaline 1,4-di-N-oxide derivatives from our in-house library. We selected them from a screening of novel inhibitors against FhCL1 and FhCL3 proteases, two essential enzymes secreted by juvenile and adult flukes. We report compounds C7, C17, C18, C19, C23, and C24 with an IC50 of less than 10 &micro, M in at least one cathepsin. We studied their binding kinetics in vitro and their enzyme-ligand interactions in silico by molecular docking and molecular dynamic (MD) simulations. These compounds readily kill newly excysted juveniles in vitro and have low cytotoxicity in a Hep-G2 cell line and bovine spermatozoa. Our findings are valuable for the development of new chemotherapeutic approaches against fascioliasis, and other pathologies involving cysteine proteases.

Apart from their anti-inflammatory action, COX inhibitors have gathered the interest of many scientists due to their potential use for the treatment and prevention of cancer. It has been shown that cyclooxygenase inhibitors restrict cancer cell growth and are able to interact with known antitumor drugs, enhancing their in vitro and in vivo cytotoxicity. The permutation of hydrophilic and hydrophobic aryl groups in COX inhibitors leads to cardinal changes in the biological activity of the compounds. In the present study, thirteen heterocyclic coxib-like 4,5-diarylfuran-3(2H)-ones and their annelated derivatives&mdash, phenanthro[9,10-b]furan-3-ones&mdash, were synthesized and studied for anti-inflammatory and COX-1/2 inhibitory action and for their cytotoxic activity on the breast cancer (MCF-7) and squamous cell carcinoma (HSC-3) cell lines. The F-derivative of the &ndash, SOMe substituted furan-3(2H)-ones exhibited the best activity (COX-1 IC50 = 2.8 &mu, M, anti-inflammatory activity (by carrageenan paw edema model) of 54% (dose 0.01 mmol/kg), and MCF-7 and HSC-3 cytotoxicity with IC50 values of 10 &mu, M and 7.5 &mu, M, respectively). A cytotoxic effect related to the COX-1 inhibitory action was observed and a synergistic effect with the anti-neoplastic drugs gefitinib and 5-fluorouracil was found. A phenanthrene derivative exhibited the best synergistic effect with gefitinib.

Herein we report the design, synthesis, molecular docking study and evaluation of antimicrobial activity of ten new dithioloquinolinethiones. The structures of compounds were confirmed by 1H NMR, 13C NMR and HPLC-HRMS. Before evaluation of their possible antimicrobial activity prediction of toxicity was performed. All compounds showed antibacterial activity against eight Gram positive and Gram negative bacterial species. All compounds appeared to be more active than ampicillin and almost all than streptomycin. The best antibacterial activity was observed for compound 8c 4,4,8-trimethyl-5-{[(4-phenyl-5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)thio]acetyl}-4,5-dihydro-1H-[1,2]dithiolo[3,4c]quino lone-1-thione). The most sensitive bacterium En.cloacae followed by S. aureus, while L.monocytogenes was the most resistant. All compounds were tested for antifungal activity also against eight fungal species. The best activity was expressed by compound 8d (5-[(4,5-Dihydro-1,3-thiazol-2-ylthio)acetyl]-4,4-dimethyl-4,5-dihydro-1H-[1,2]dithiolo[3,4-c]quinoline-1-thione). The most sensitive fungal was T. viride, while P. verrucosum var. cyclopium was the most resistant one. All compounds were more potent as antifungal agent than reference compound bifonazole and ketoconazole. The docking studies indicated a probable involvement of E. coli DNA GyrB inhibition in the anti-bacterial mechanism, while CYP51ca inhibition is probably responsible for antifungal activity of tested compounds. It is interesting to mention that docking results coincides with experimental.

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.

A series of 21 novel N-[2-phenyl-4-oxo-1,3-thiazolidin-3-yl]-1,2-benzothiazole-3-carboxamides/acetamides (4a–4p) as well as a series of N′-(halophenylmethylidene)-1,2-benzothiazole-3-acetohydrazides (3h–3p) have been synthesized and evaluated for their antimicrobial activity against eight bacterial and eight fungal species, among them plant, animal and human pathogens and food contaminating species. All compounds appeared to be potent and the best activity was exhibited by compound 4d with MIC in the range of 10.7–21.4 μmol mL−1 × 10−2 and MBC of 21.4–40.2 μmol mL−1 × 10−2. The best antifungal activity was observed for compounds 4p and 3h. Elucidation of the relationship between the antimicrobial activity and molecular properties of the synthesized compounds was also performed. Synthetic intermediates were also tested with several exhibiting good antimicrobial activities. Docking studies for some compounds were performed.

A series of substituted thiazole-bisphosphonates and relevant bisphosphonic acid counterparts was synthesized from the reaction of 2-chloro-N-(substituted)thiazole acetamides with tetraethyl methylene-1,1-bisphosphonate reagent in the presence of a base. The reactions proceeded smoothly via nucleophilic substitution to give our targets in good to high yields. Among the products, 4 bisphosphonic acids exhibited excellent anticancer activity vs four tested carcinoma cell lines (MCF7, HELA, DU-145, and HCT-116) with GI50 values ranging from 1.8 to 4.8 μMmL−1. According to the prediction results (using PASS program), the same acids and their BP-analogs were also evaluated for their anti-inflammatory properties. The acute carrageenan induced paw edema in rats model was used and the tested compounds showed notable anti-inflammatory potency without toxicity side effects.

2,2’-dihydroxybenzophenones and derivatives have been synthesized directly or by oxidation of their incipiently obtained benzylic alcohols by diverse efficient methods. Oxime and N-acyl hydrazone derivatives have also been prepared. Their structure profile has been scrutinized by DFT/B3LYP-6-311++G** methodology, NMR spectroscopy and dihedral angle grid scan analysis. Energetically favorable conformations pointed to (i) an almost coplanar bifurcated 6-membered H bridge in ketones, (ii) a single 6-membered H bridge, accompanied by a 7-membered H bonding interaction in oximes and (iii) a single 6-membered H-bridge in hydrazones. In the latter case, a stable conformation with an additional 9-membered pseudo ring was also found. Highly deshielded protons in the NMR spectra are in accordance with the theoretically obtained findings on the H-bonded conformers. Significant anti-inflammatory activity of the compounds has been found by in vivo tests with their oxime and hydrazone derivatives showing the highest activity, hydrazone 11, in partucular, competing with marketed drugs. In silico docking studies point to the perspective potency of these structures as COX-1/COX-2 inhibitors.

By reaction with sodium ethoxide and as a function of their structures, 2-[(1-alkyl(aryl)-4-cyano-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl)oxy]acetamides gave 1-amino-5-alkyl(aryl)-7,8-dihydro-6H-cyclopenta[d]furo[2,3-b]pyridine-2-carboxamides and/or 1-alkyl(aryl)-3-amino-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitriles .

Starting from 7(8)-chlorofuro(thieno)[3,2- d ]pyrimidines 1 , the corresponding 7(8)-hydrazinofuro(thieno)[3,2- d ]pyrimidines 2 were obtained by reaction with hydrazine. By treatment with nitrous acid, compounds 2 gave fused furo- and thieno[2,3- e ]tetrazolo[1,5- c ]pyrimidines 3 T and 4 T in excellent yields, which in solution exist in equilibrium with 7(8)-azidofuro(thieno)[3,2- d ]pyrimidines 3 A and 4 A . Compounds 3 T / 3 A and 4 T / 4 A represent useful substrates for investigating the azide/tetrazole equilibrium: it has been examined as a function of solvent, temperature, and their structure. We have observed that, in solution, in both 3 and 4 the equilibrium was strongly affected by the solvent used. In contrast, X-ray analysis has shown that both thieno[2,3- e ]tetrazolo[1,5- c ]pyrimidines and furo[2,3- e ]tetrazolo[1,5- c ]pyrimidines in solid state exist only in the tetrazole tautomeric form. For this reason the equilibrium constants and the relevant thermodynamic parameters have been calculated in different solvents: finally excellent logarithmic plots of Δ G ° values versus dielectric constants have been observed (slopes 10.00÷10.57; correlation coefficients 0.9962÷0.9999) for a series (seven examples) of furo compounds 3 .

Background: Inflammation is a complex response to noxious stimuli promoted by the release of chemical mediators from the damaged cells. Metabolic products of arachidonic acid, produced by the action of cyclooxygenase and lipoxygenase, play important roles in this process. Several non-steroidal anti-inflammatory drugs act as cyclooxygenase inhibitors. However, almost all of them have undesired side effects. Methods: Prediction of the anti-inflammatory action of the compounds was performed using PASS Program. The anti-inflammatory activity was evaluated by the carrageenan paw edema test. COX and LOX inhibitory actions were tested using ovine COX-1, human recombinant COX-2 and soybean LOX-1, respectively. Docking analysis was performed using Autodock. Results: All designed derivatives had good prediction results according to PASS and were synthesized and experimentally evaluated. The compounds exhibited in vivo anti-inflammatory action with eleven being equal or better than indomethacin. Although, some of them had no or low inhibitory effect on COX-1/2 or LOX, certain compounds exhibited COX-1 inhibition much higher than naproxen and COX-2 inhibition, well explained by Docking analysis. Conclusions: A number of compounds with good anti-inflammatory action were obtained. Although, some exhibited remarkable COX inhibitory action this activity did not follow the anti-inflammatory results, indicating the implication of other mechanisms.