The Role of Vitamins, Magnesium, and Trace Elements in COVID-19 Treatment and Post-COVID-19 Rehabilitation: An Updated Overview.

This review summarizes the scientific knowledge concerning the impact of vitamins, magnesium, and trace elements on various mechanisms contributing to the possible treatment and prevention of COVID-19, including its delayed consequences. A search was conducted in various databases, including PubMed, Scopus, ClinicalTrials.- gov, and Web of Science. Among the main mechanisms involved in the effects of the studied micronutrients, immune-boosting, antioxidant and anti-inflammatory effects were also highlighted. The analyzed clinical trials confirmed that supplementation with higher daily doses of some micronutrients can reduce SARS-CoV-2 viral load and hospitalization time. The potential role of most known vitamins in preventing, treating COVID-19, and rehabilitating patients was considered. The most promising agents for combating COVID-19 and its consequences might be the following vitamins: vitamin D, ascorbic acid, polyunsaturated fatty acids (PUFAs), and some B complex vitamins. Inorganic elements deserving attention include magnesium and trace elements, such as zinc, selenium, copper, and iron. Some associations were found between micronutrient deficiencies and COVID-19 severity in children, adults, and older people. Patients can obtain the aforementioned micronutrients from natural food sources or as supplements/- drugs in various dosage forms. The reviewed micronutrients might be considered adjunctive treatment strategies for COVID-19 patients.

4-Thiazolidinone derivative Les-3833 effectively inhibits viability of human melanoma cells through activating apoptotic mechanisms.

AIM: To evaluate cytotoxic action of 4-thiazolidinone derivative Les-3833 and study the mechanisms of its pro-apoptotic action toward human melanoma cells and human tumor cell lines of other tissue origin. METHODS: The effect of Les-3833 or doxorubicin on the viability of 9 cell lines was studied using MTT assay, while human melanoma cells of WM793 line were additionally examined using light and fluorescent microscopies for evaluating cytomorphological changes. The Western-blot and flow cytometric analyses were carried out to study signaling pathways of melanoma cell cycling and death. RESULTS: Les-3833 was the most efficient against melanoma cells. Its half maximal inhibitory concentration (IC50) was 0.22 µg/mL for WM793 cells and 0.3 µg/mL for SK-Mel-28 melanoma cells. For human lung A549, breast MCF-7, colon HCT116, and ovarian SKOV3 carcinoma cell lines IC50 was in between 2.5 to >5.0 µg/mL. Les-3833 was relatively not toxic (IC50 > 5 µg/mL) for human embryonic kidney HEK293 cells. Results of Annexin V/PI staining of melanoma cells and activation of caspase 3, PARP, MAPK, and EndoG protein suggest apoptosis in Les-3833-treated cells. Les-3833 also induced ROS production in melanoma cells and their arrest in G0/G1 phase of cell cycle. CONCLUSION: Novel 4-thiazolidinone derivative Les-3833 is effective against human melanoma cells in vitro, and such effect is tumor specific since it is much less pronounced in human carcinoma and leukemia cells. In melanoma cells Les-3833 induces apoptosis (morphological changes and increased pro-apoptotic proteins), ROS production, and arrest in G0/G1 phase of cell cycle.

Synthesis and evaluation of anticancer activity of 5-ylidene-4- aminothiazol-2(5H)-one derivatives.

The synthesis and antitumor activity screening of 4-aminothiazol-2(5H)-one derivatives were performed. The absence of possible 4-amino-imino tautomerism of thiazolidinones-2 has been confirmed based on the study of the molecule structures. The existence of the alone amino-form was confirmed. An anticancer activity screening was performed within the Developmental Therapeutics Program (National Cancer Institute/NIH, USA). Tested compounds possess low to moderate anticancer activity (average values - 60 cancer cell lines assay) with significant selective action on certain cancer cell lines (CCRF-CEM and RPMI-8226/leukemia, U251/CNS cancer, RFX 393/renal cancer, OVCAR/ovarian cancer etc.). The advantage of 5-ylidene-4-R-amino derivatives in comparison with compounds with free amino group was shown. Some structure-activity findings, the comparison of target compounds with isomeric 5-ylidene-2-imino(amino)thiazol-4(5H)-ones, as well as COMPARE analysis were described. Among the tested compounds (Z)-5-(furan-2-ylmethylidene)-4-(4-chlorophenylamino)thiazol-2(5H)-one (IIIk) and (Z)-5-(4-diethylaminophenylmethylidene)-4-(4-hydroxy-5-isopropyl-2-methylphenylamino)thiazol-2(5H)-one (IIIp) possessed the highest levels of activity.

Synthesis of pyrazoline-thiazolidinone hybrids with trypanocidal activity.

A series of novel 4-thiazolidinone-pyrazoline conjugates have been synthesized and tested for anti-Trypanosoma brucei activity. Screening data allowed us to identify five thiazolidinone-pyrazoline hybrids, which possess promising trypanocidal activity, with IC50 ≤ 1.2 µM. The highest active thiazolidinone-pyrazoline conjugates 3c and 6b (IC50 values of 0.6 µM and 0.7 µM, respectively) were 6-times more potent antitrypanosomal agents than nifurtimox. In addition, these compounds, as well as 6d and 6e had selectivity index higher than 50, and were more selective than nifurtimox. SAR study included substituent variations at the pyrazoline moiety, modifications of N3 position of the thiazolidinone portion, elongation of the linker between the heterocycles, as well as rhodanine-isorhodanine isomerism. It was also shown that methyl or aryl substitution at the thiazolidinone N3-position is crucial for trypanocidal activity.

Synthesis and Anticancer Activity of New Thiopyrano[2,3-d]thiazoles Based on Cinnamic Acid Amides.

Novel rel-(5R,6S,7S)-2-oxo-5-phenyl-7-aryl(hetaryl)-3,7-dihydro-2H-thiopyrano [2,3-d]thiazole-6-carboxylic acid amides were synthesized in a hetero-Diels-Alder reaction with a series of cinnamic acid amides. The synthesized compounds were tested for their anticancer activity in vitro in the standard National Cancer Institute 60 cancer cell line assay. Promising compounds 3e, 3g, and 3h with moderate antitumor activity were identified among the synthesized series.

Computational Search for Possible Mechanisms of 4-Thiazolidinones Anticancer Activity: The Power of Visualization.

Public databases of NCI-60 tumor cell line screen results and measurements of molecular targets in the NCI-60 panel give the opportunity to assign possible anticancer mechanism to compounds with positive outcome from antitumor assay. Here, the novel protocol of NCI databases mining where inferences are based on the visualization is presented and utilized with the aim to identify putative biological routes of 4-thiazolidinones anticancer effect. As a result, highly potent 4-thiazolidinone-pyrazoline-isatin conjugates show the similarity of activity patterns with puromycin and CBU-028 and their pattern is also highly correlated with fraction of methylated CpG sites in CD34, AF5q31 and SYK. Several compounds from this group show strong negative correlation with fraction of methylated CpG sites in HOXA5. Thiopyrano[2,3-d][1,3]thiazol-2-ones bearing naphtoquinone fragment were found to possess the same activity pattern as fusarubin does. But none of the studied 4-thiazolidinone derivatives has activity fingerprint similar to standard anticancer agents. The obtained results bring medicinal chemistry closer to the understanding of basic nature of 4-thiazolidinones effect on cancer cells.

Synthesis and Biological Activity of New Thiopyrano[2,3-d]thiazoles Containing a Naphthoquinone Moiety.

Novel 11-substituted 3,11-dihydro-2H-benzo[6,7]thiochromeno[2,3-d][1,3]-thiazole-2,5,10-triones 4a-i were synthesized in 75-90% yields via the hetero-Diels-Alder reaction of 5-arylidene-4-thioxo-2-thiazolidinones with 1,4-naphthoquinone. The synthesized compounds were evaluated for their antineoplastic and antimycobacterial activities. A moderate selectivity against melanoma cancer cells (GI50 (UACC-257-melanoma) = 0.22 µM) was demonstrated for 4i, whereas derivatives 4a, 4c, 4g, and 4h showed promising antimycobacterial activity at a low toxicity level.

Synthesis and biological activity evaluation of 5-pyrazoline substituted 4-thiazolidinones.

A series of novel 5-pyrazoline substituted 4-thiazolidinones have been synthesized. Target compounds were evaluated for their anticancer activity in vitro within DTP NCI protocol. Among the tested compounds, the derivatives 4d and 4f were found to be the most active, which demonstrated certain sensitivity profile toward the leukemia subpanel cell lines with GI50 value ranges of 2.12-4.58 µM (4d) and 1.64-3.20 µM (4f). The screening of antitrypanosomal and antiviral activities of 5-(3-naphthalen-2-yl-5-aryl-4,5-dihydropyrazol-1-yl)-thiazolidine-2,4-diones was carried out with the promising influence of the mentioned compounds on Trypanosoma brucei, but minimal effect on SARS coronavirus and influenza types A and B viruses.

Synthesis of new 4-thiazolidinone-, pyrazoline-, and isatin-based conjugates with promising antitumor activity.

The synthesis and antitumor activity screening of novel 3-[2-(3,5-diaryl-4,5-dihydropyrazol-1-yl)-4-oxo-4,5-dihydro-1,3-thiazol-5-ylidene]-2,3-dihydro-1H-indol-2-ones 1-23 and 3-(3,5-diarylpyrazol-1-yl)-2,3-dihydro-1H-indol-2-ones 24-39 are performed. In vitro anticancer activity of the synthesized compounds was tested by the National Cancer Institute. Most of them displayed anticancer activity on leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate, and breast cancers cell lines. The structure-activity relationship is discussed. The most effective anticancer compound 10 was found to be active with mean GI50 and TGI values of 0.071 µM and 0.76 µM, respectively. It demonstrated the highest antiproliferative influence on the non-small-cell lung cancer cell line HOP-92 (GI50 < 0.01 µM), colon cancer line HCT-116 (GI50 = 0.018 µM), CNS cancer cell line SNB-75 (GI50 = 0.0159 µM), ovarian cancer cell line NCI/ADR-RES (GI50 = 0.0169 µM), and renal cancer cell line RXF 393 (GI50 = 0.0197 µM).

Biologically active 4-thiazolidinones: a review of QSAR studies and QSAR modeling of antitumor activity.

4-Thiazolidinone is a promising scaffold for the search of new potential antibacterial, antiviral, antidiabetic and anticancer agents etc. SAR analysis of the most potent compounds and different activities evaluation provide a solid background for de novo design of novel drugs. Current review summarizes recent QSAR studies on the 4-thiazolidinones making the emphasis on both technical and interpretative sides of reported models. Several papers among them are devoted to the anticancer activity of 4-thiazolidinone derivatives and are reporting QSAR models that were obtained via multiple linear regressions (MLR). Additionally, a non-linear approach, namely Gaussian processes, has been applied to identify the relationships between 4-thiazolidinones structure and tumor cell growth inhibition. The interpretation of the reported model highlights the core template for the design of new highly-potent anticancer agents and proposes a hypothesis about key role of Hydrogen at the N-atom three bonds away from thiazolidine in the interaction with biotarget.

Synthesis and anticancer activity of isatin-based pyrazolines and thiazolidines conjugates.

The synthesis and antitumor activity screening of novel isatin based conjugates with thiazolidine and pyrazoline moieties were performed. Reaction of 3,5-diaryl-4,5-dihydropyrazoles with chloroacetyl chloride yielded starting 2-chloro-1-(3,5-diaryl-4,5-dihydropyrazol-1-yl)-ethanones which were utilized in alkylation of isatin and 5-bromoisatin. Thus, corresponding 1-[2-(3,5-diaryl-4,5-dihydropyrazol-1-yl)-2-oxoethyl]-1H-indole-2,3-diones (1a-1d) have been obtained. The compounds 1a-1d have been used in Knoevenagel condensation with 4-thiazolidinones for obtaining a series of 5-ylidenederivatives 2a-2f and 3a-3d. The synthesized compounds were tested for their anticancer activity in NCI60 cell lines. Among the tested compounds, 5-bromo-1-{2-[5-(4-chlorophenyl)-3-(4-methoxyphenyl)-4,5-dihydropyrazol-1-yl]-2-oxoethyl}-1H-indole-2,3-dione (1d) was found to be the most active candidate with selective influence on leukemia subpanel tumor cell lines with GI(50) values range of 0.69-3.35 µM.

Synthesis and anticancer activity evaluation of 4-thiazolidinones containing benzothiazole moiety.

Antitumor screening of several novel 4-thiazolidinones with benzothiazole moiety has been performed. Reactions of (benzothiazole-2-yl)hydrazine with trithiocarbonyl diglycolic acid or 6-methyl-2-aminobenzothiazole with 2-carbethoxymethylthio-2-thiazoline-4-one have yielded starting 3- (1) or 2-substituted (11) 4-thiazolidinones which have been subsequently utilized in a Knoevenagel condensation for obtaining a series of 5-arylidene derivatives 2-10, 12-16. Compound 11 has been obtained alternatively by a counter synthesis method based on the reaction of 2-chloro-N-(6-methylbenzothiazol-2-yl)-acetamide and ammonium thiocyanate. The structures of compounds have been determined by (1)H, (13)C NMR, IR and X-ray analysis. In vitro anticancer activity of the synthesized compounds was tested by the National Cancer Institute and two (6, 16) of them has revealed the anticancer activity on leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate and breast cancers cell lines. Among tested compounds, 2-{2-[3-(benzothiazol-2-ylamino)-4-oxo-2-thioxothiazolidin-5-ylidenemethyl]-4-chlorophenoxy}-N-(4-methoxyphenyl)-acetamide (6) was found to be the most active candidate with average logGI(50) and logTGI values -5.38 and -4.45 respectively.

Synthesis of 5-arylidene-2-amino-4-azolones and evaluation of their anticancer activity.

Series of novel 5-arylidene-2-arylaminothiazol-4(5H)-ones and 2-aryl(benzyl)amino-1H-imidazol-4(5H)-ones were synthesized from appropriate 2-alkylthioazol-4-ones using nucleophilic substitution in position 2 by various anilines and benzylamines and Knoevenagel reaction. X-ray structural studies of 22 revealed the structure to be intermediate between amino and imino tautomeric forms. All the target compounds were evaluated for the anticancer activity in vitro in standard National Cancer Institute 60 cancer cell lines assay. Majority of compounds showed significant antitumor cytotoxicity effect at micromolar and submicromolar level (Mean LogGI50 ranges -5.77 to -4.35). Some of the most potent compounds, namely 10 and 13, possessed selectively high effect on all leukemia cell lines at submicromolar level (Mean LogGI50 [leukemia lines], respectively, -6.41 and -6.29), which are probably associated with immunosuppressive activity. Individual cancer cell lines sensitivity to synthesized compounds and SAR studies are discussed. COMPARE analysis allowed to disclose probable modes of anticancer action for synthesized compounds, in particular showed number of high correlations with activity patterns of alkylating agents (PCC approximately 0.606-0.731).

Synthesis and in vitro anticancer activity of 2,4-azolidinedione-acetic acids derivatives.

The synthesis and evaluation of anticancer activity of 2,4-thia(imida)zolidinedione-3- and 5-acetic acids amides were described. The structures of compounds were determined by IR, (1)H NMR, and MS analysis. In vitro anticancer activity of these compounds has been tested in National Cancer Institute (NCI) and the relationships between structure and anticancer activity are discussed. Among 2,4-azolidinedione-acetic acids derivatives 2-[5-(4-chlorobenzylidene)-2,4-dioxo-imidazolidin-3-yl]-N-(2-trifluoromethyl-phenyl)-acetamide (Ic) was superior to other related compounds in terms of high selectivity for the leukemia CCRF-CEM (logGI(50)=-6.06), HL-60(TB) (logGI(50)=-6.53), MOLT-4 (logGI(50)=-6.52) and SR (logGI(50)=-6.51) cell lines.

Synthesis of novel thiazolone-based compounds containing pyrazoline moiety and evaluation of their anticancer activity.

To examine the anticancer activity several novel thiazolone-based compounds containing 5-aryl-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl framework were obtained. Reaction of 5-aryl-3-phenyl-4,5-dihydropyrazole with 4-thioxo-2-thiazolidinone or 2-carbethoxymethylthio-2-thiazoline-4-one yielded starting 4- (1 and 2) or 2-substituted (11 and 12) thiazolones which were utilized in Knoevenagel condensation for obtaining a series of 5-arylidene derivatives 3-10, 13-18. Alternatively 11, 12 and their 5-arylidene derivatives were synthesized by means of 3-phenyl-5-aryl-1-thiocarbamoyl-2-pyrazoline as S,N-binucleophile via [2+3]-cyclocondensation approach. The structures of compounds were determined by (1)H, (13)C NMR, LC-MS, EI-MS and X-ray analysis. The in vitro anticancer activity of synthesized compounds were tested by the National Cancer Institute and most of them displayed anticancer activity on leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate and breast cancer cell lines. Relations between structure and activity are discussed, the most efficient anticancer compound 16 was found to be active with selective influence on colon cancer cell lines, especially on HT 29 (logGI(50)=-6.37).

Anticancer thiopyrano[2,3-d][1,3]thiazol-2-ones with norbornane moiety. Synthesis, cytotoxicity, physico-chemical properties, and computational studies.

A series of novel 9-substituted-3,7-dithia-5-azatetracyclo[9.2.1.0(2,10).0(4,8)]tetradecen-4(8)-ones-6 have been synthesized by a stereoselective hetero-Diels-Alder reaction of 5-ylidene-4-thioxo-2-thiazolidone derivatives with norbornene-2. All the compounds have been evaluated for antitumor activity in in vitro human tumor cell lines, and 10 of them possessed significant and selective cytotoxicity (MGM logGI50 approximately -4.17 to -4.98, for individual cell lines logGI50 up to -8). COMPARE analyses of differential growth inhibition patterns of compounds at the GI50 level showed high correlations with some of the antitubulin agents. The lipophilicity of the compounds was studied by RP-TLC and found to correlate well with calculated logP values. Docking and structure-activity relationship studies produced seven QSAR models with 2 or 3 variables, with correlation coefficients r2>0.9 and leave-one-out cross-validation correlation coefficients, q2>0.8.