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Carbonic Anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide involved in several biological processes. They show a wide diversity in tissue distribution and their subcellular localization. Twenty-two novel phthalazine derivatives were designed, synthesized, and evaluated against four human isoforms: hCA I, hCA II, hCA IX, and hCA XII. Compounds appeared to be very active mostly against hCA IX (7) and hCA I (6) isoforms being more potent than reference drug acetazolamide (AAZ). Some compounds appeared to be very selective with a selectivity index up to 13.8. Furthermore, docking was performed for some of these compounds on all isoforms to understand the possible interactions with the active site. Additionally, the most active compounds against hCA IX were subjected to cell viability assay. The anticancer activity of the compounds (3 a-d, 5 d, 5 i, and 5 m) was investigated using two human breast cancer cell lines, i. e. MCF-7 and MDA-MB-231 cells, and the normal counterpart, namely MCF10-A cells., (© 2024 Wiley-VCH GmbH.)

Continuing our studies in the field of new heterocyclic compounds with biological interest, herein we report the synthesis and anticancer activity of new N- and S-substituted derivatives of tetracyclic pyrido[3',2' : 4,5]thieno[3,2-d]pyrimidines. In this regard, starting from the thieno[2,3-b]pyridine-2-carboxylates, the corresponding 8(9)-aminopyrido[3',2' : 4,5]thieno[3,2-d]pyrimidin-7(8)-ones, as well as chloro derivatives were obtained. Based on the latter, amino, hydrazino and S-alkyl derivatives of pyrido[3',2' : 4,5]thieno[3,2-d]pyrimidines were synthesized subsequently. The current study focuses on identifying the potential of thieno[3,2-d]pyrimidine derivatives primarily towards ATR kinase inhibition, through computational predictions, followed by synthesis and cancer cell viability studies, along with an aim to develop the core as PIKK inhibitors for cancer therapy., (© 2024 The Authors. Chemistry & Biodiversity published by Wiley-VHCA AG, Zurich, Switzerland.)

Major obstacles faced by the use of nonsteroidal anti-inflammatory drugs (NSAID) are their gastrointestinal toxicity induced by non-selective inhibition of both cyclooxygenases (COX) 1 and 2 and their cardiotoxicity associated with a certain class of COX-2 selective inhibitors. Recent studies have demonstrated that selective COX-1 and COX-2 inhibition generates compounds with no gastric damage. The aim of the current study is to develop novel anti-inflammatory agents with a better gastric profile. In our previous paper, we investigated the anti-inflammatory activity of 4-methylthiazole-based thiazolidinones. Thus, based on these observations, herein we report the evaluation of anti-inflammatory activity, drug action, ulcerogenicity and cytotoxicity of a series of 5-adamantylthiadiazole-based thiazolidinone derivatives. The in vivo anti-inflammatory activity revealed that the compounds possessed moderate to excellent anti-inflammatory activity. Four compounds 3 , 4 , 10 and 11 showed highest potency (62.0, 66.7, 55.8 and 60.0%, respectively), which was higher than the control drug indomethacin (47.0%). To determine their possible mode of action, the enzymatic assay was conducted against COX-1, COX-2 and LOX. The biological results demonstrated that these compounds are effective COX-1 inhibitors. Thus, the IC 50 values of the three most active compounds 3 , 4 and 14 as COX-1 inhibitors were 1.08, 1.12 and 9.62 μΜ, respectively, compared to ibuprofen (12.7 μΜ) and naproxen (40.10 μΜ) used as control drugs. Moreover, the ulcerogenic effect of the best compounds 3 , 4 and 14 were evaluated and revealed that no gastric damage was observed. Furthermore, compounds were found to be nontoxic. A molecular modeling study provided molecular insight to rationalize the COX selectivity. In summary, we discovered a novel class of selective COX-1 inhibitors that could be effectively used as potential anti-inflammatory agents.

Despite extensive studies and the great variety of existing anticancer agents, cancer treatment remains an aggravating and challenging problem. Therefore, the development of novel anticancer drugs with a better therapeutic profile and fewer side effects to combat this persistent disease is still necessary. In this study, we report a novel series of benzothiazole and chromone derivatives that were synthesized and evaluated for their anticancer activity as an inhibitor of ATR kinase, a master regulator of the DDR pathway. The cell viability of a set of 25 compounds was performed using MTT assay in HCT116 and HeLa cell lines, involving 72 h incubation of the compounds at a final concentration of 10 µM. Cells incubated with compounds 2c , 7h and 7l were found to show viability ≤50%, and were taken forward for dose-response studies. Among the tested compounds, three of them ( 2c , 7h and 7l ) showed higher potency, with compound 7l exhibiting the best IC 50 values in both the cell lines. Compounds 2c and 7l were found to be equally cytotoxic towards both the cell lines, namely, HCT116 and HeLa, while compound 7h showed better cytotoxicity towards HeLa cell line. For these three compounds, an immunoblot assay was carried out in order to analyze the inhibition of phosphorylation of Chk1 at Ser 317 in HeLa and HCT116 cells. Compound 7h showed inhibition of pChk1 at Ser 317 in HeLa cells at a concentration of 3.995 µM. Further analysis for Chk1 and pChk1 expression was carried out in Hela cells by treatment against all the three compounds at a range of concentrations of 2, 5 and 10 µM, wherein compound 7h showed Chk1 inhibition at 2 and 5 µM, while pChk1 expression was observed for compound 7l at a concentration of 5 µM. To support the results, the binding interactions of the compounds with the ATR kinase domain was studied through molecular docking, wherein compounds 2c , 7h and 7l showed binding interactions similar to those of Torin2, a known mTOR/ATR inhibitor. Further studies on this set of molecules is in progress for their specificity towards the ATR pathway.

Continuing our research in the field of new heterocyclic compounds, herein we report on the synthesis and antitumor activity of new amino derivatives of pyrido[3',2':4,5](furo)thieno[3,2- d ]pyrimidines as well as of two new heterocyclic systems: furo[2- e ]imidazo[1,2- c ]pyrimidine and furo[2,3- e ]pyrimido[1,2- c ]pyrimidine. Thus, by refluxing the 8-chloro derivatives of pyrido[3',2':4,5]thieno(furo)[3,2- d ]pyrimidines with various amines, the relevant pyrido[3',2':4,5]thieno(furo)[3,2- d ]pyrimidin-8-amines were obtained. Further, the cyclization of some amines under the action of phosphorus oxychloride led to the formation of new heterorings: imidazo[1,2- c ]pyrimidine and pyrimido[1,2- c ]pyrimidine. The possible antitumor activity of the newly synthesized compounds was evaluated in vitro. The biological tests evidenced that some of them showed pronounced antitumor activity. A study of the structure-activity relationships revealed that the compound activity depended mostly on the nature of the amine fragments. A docking analysis was also performed for the most active compounds., Competing Interests: The authors declare no conflicts of interest.

Background: Pharmacological effects of biologically active "small molecules" can be improved by their targeted modification, which affects drug delivery and interaction with tumor cells and microorganisms. We aimed to evaluate anticancer and antimicrobial activity of lipid-like choline derivatives modified via simultaneous introduction of tetrahydro(iso)quinoline based pharmacophore system at nitrogen atom and long chain alkyl substituent at oxygen atom., Methods: Target compounds were synthesized under phase-transfer catalysis conditions followed by quaternization, and evaluated for cytotoxicity and NO-generation ability on HT-1080 and MG-22A tumor cell lines and NIH 3T3 normal mouse fibroblasts, and screened for antimicrobial activity against gram-positive (Staphylococcus aureus and Bacillus cereus) and gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa and Proteus mirabilis) and fungi (Candida albicans and Aspergillus niger). Inhibitory action of active compounds towards E. coli DNA gyrase was investigated., Results: Target compounds exhibit high selective cytotoxicity (LC 50 <1μg/mL) and NO-induction ability, and reveal strong antimicrobial activity with MIC and MBC/MFC values of 0.5-32μg/mL, predominantly vs. gram-positive bacteria and fungi. Tested substances displayed inhibitory effect towards E. coli DNA gyrase, though less than ciprofloxacin. Tetrahydroisoquinoline derivatives and compounds possessing substituents with chain length of 10 and 11 carbon atoms have highest indices of activities., Conclusions: Lipid-like N-heterocyclic choline analogues based on 1,2,3,4-tetrahydro(iso)quinoline scaffold, possessing very high cytotoxicity with attendant strong antimicrobial activity are the leads for developing effective dual action therapeutics., (Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

A series of new N-[(benzo)thiazol-2-yl]-2/3-[3,4-dihydroisoquinolin-2(1H)-yl]ethan/propanamide derivatives was synthesized and characterized by (1)H, (13)C NMR and IR spectroscopy and mass-spectrometry. A single crystal X-ray study of N-(1,3-benzothiazol-2-yl)-2-[3,4-dihydroisoquinolin-2(1H)-yl]ethanamide is reported to determine its conformational feature. The investigated compounds were found to be active in psychotropic in vivo, anti-inflammatory in vivo and cytotoxicity in vitro screening. They possess marked sedative action, reveal high anti-inflammatory activity, have selective cytotoxic effects and NO-induction ability concerning tumour cell lines. Some of the compounds synthesized demonstrate antimicrobial action. An attempt was made to correlate the biological results with their structural characteristics and physicochemical parameters. Some specific combinations of types of activities for the synthesized compounds have been revealed., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Methods for the preparation of various aminomethylene bisphosphonates were developed. The required bisphosphonates were obtained by applying tetraethyl methylenebisphosphonate reagent to different types of oxazinones and the relevant Schiff base derivatives. Based on the prediction results (Pass program), we further estimated the sister chromatid exchange frequency and proliferation rate index values of human lymphocyte cultures after the administration of four newly synthesized bisphosphonates in order to evaluate their cytotoxic/cytostatic and possible antineoplastic potency. The results showed that all four bisphosphonates cause a dose-dependent increase in sister chromatid exchange frequency, followed by a decrease in proliferation rate index in both experiments compared to the control., (© 2012 John Wiley & Sons A/S.)

A new series of S,N-bisphosphonate derivatives was synthesized and evaluated as antitumor agents against breast-, cervix-, liver, and colon cancer diseases. Antiarthritic and antichronic inflammatory properties of the new bisphosphonates (BPs) were also investigated. The studies demonstrated an efficient site selective method for making condensation products of BP-derivatives in high yields from thiazinethiones and tetraethyl methylenebisphosphonate reagent. The bioscreening evaluation showed that one of the tested BPs exhibited remarkable antitumor activity against the four tested carcinoma cell lines; nevertheless, all tested S,N-BP-derivatives (11 compounds) showed significant to moderate anti-inflammatory activity and capable of inhibiting polyarthritis., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

With the aim to identify novel inhibitors of parasitic nematode thymidylate synthase (TS), we screened in silico an in-house library of natural compounds, taking advantage of a model of nematode TS three-dimensional (3D) structure and choosing candidate compounds potentially capable of enzyme binding/inhibition. Selected compounds were tested as (i) inhibitors of the reaction catalyzed by TSs of different species, (ii) agents toxic to a nematode parasite model (C. elegans grown in vitro), (iii) inhibitors of normal human cell growth, and (iv) antitumor agents affecting human tumor cells grown in vitro. The results pointed to alvaxanthone as a relatively strong TS inhibitor that causes C. elegans population growth reduction with nematocidal potency similar to the anthelmintic drug mebendazole. Alvaxanthone also demonstrated an antiproliferative effect in tumor cells, associated with a selective toxicity against mitochondria observed in cancer cells compared to normal cells. [ABSTRACT FROM AUTHOR]

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—phenanthro[9,10-b]furan-3-ones—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 –SOMe substituted furan-3(2H)-ones exhibited the best activity (COX-1 IC50 = 2.8 μM, 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 μM and 7.5 μM, 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. [ABSTRACT FROM AUTHOR]

Protein kinase CK2 is an emerging target for therapeutic intervention in human diseases, particularly in cancer. Inhibitors of this enzyme are currently in clinical trials, indicating the druggability of human CK2. By virtual screening of the ZINC database, we found that the natural compound bikaverin can fit well in the ATP binding site of the target enzyme CK2. By further in vitro evaluation using CK2 holoenzyme, bikaverin turned to be a potent inhibitor with an IC50 value of 1.24 µM. In this work, the cell permeability of bikaverin was determined using a Caco-2 cell permeability assay as a prerequisite for cellular evaluation and the compound turned out to be cell permeable with a Papp- value of 4.46 × 10−6 cm/s. Bikaverin was tested for its effect on cell viability using a MTT assay and cell proliferation using an EdU assay in different cancer cell lines (MCF7, A427 and A431 cells). Cell viability and cell proliferation were reduced dramatically after treatment with 10 µM bikaverin for 24 h. Additionally the IncuCyte® live-cell imaging system was applied for monitoring the cytotoxicity of bikaverin in the three tested cancer cell lines. Finally, molecular dynamic studies were performed to clarify the ligand binding mode of bikaverin at the ATP binding site of CK2 and to identify the amino acids involved. [ABSTRACT FROM AUTHOR]