Синтез, перетворення та біологічна активність поліциклічних конденсованих систем на основі 4-тіазолідонів

The dissertation is dedicated to search of new biologically active substances among polycyclic fused systems based on 4-thiazolidones using the methodology of organic synthesis, traditional and high-throughput pharmacological screening, QSAR-analysis, molecular docking and lipophilicity studies.

Interaction of acrolein, dimethyl acetylenedicarboxylate, N-carboxymethylmaleimide, aroylacrylic acids, 2-norbornene, 5-norbornene-2,3-dicarboxylic acid imides and 1,4-naphtoquinone in hetero-Diels-Alder reaction with 5-(R-methylidene)isorhodanines selectively yields functionally substituted thiopyrano[2,3-d]thiazoles. The latter allowed to obtain 199 fused derivatives based on 4-thiazolidones, elucidate their structure and study their physico-chemical parameters as well as biological activity.

Interpreting of heteronuclear NMR ¹Н-¹³С correlations (methods HMQC and НМВС) allowed to establish, that interaction of 5-(R-methylidene)-4-thioxo-2-thiazolidones with aroylacrylic acids selectively yields 6-aroyl-2-oxo-7-aryl(hetaryl)-3,5,6,7-tetrahydro-2Н-thiopyrano[2,3-d]thiazole-5-carboxylic acids.

Stereo-configuration of 9-aryl-3,7-dithia-5-azatetracyclo[9.2.1.0^2,10.0^4,8]tetradecen-4(8)-ones-6, obtained via interaction of 2-norbornene with 5-arylideneisorhodanines, have been elucidated by means of X-Ray analysis.

[4+2]-Adducts of 5-(R-methylidene)-4-thioxo-2-thiazolidones reaction with 1,4-naphtoquinone undergo spontaneous oxidation, which allowed to obtain new non-described in chemical literature 3,5,10,11-tetrahydro-2H-benzo[6,7]thiocromeno[2,3-d]thiazol-2,5,10-triones, which contained biophore fragments of anticancer drugs adriamycin, daunorubicin, mitoxantrone and mitomicin С.

It was identified that 5-alkylidene-4-thioxo-2-thiazolidones are active heterodienes in hetero-Diels-Alder reaction. This allowed following their interaction with N-substituted maleimides, aroylacrylic acids, 2-norbornene, 5-norbornene-2,3-dicarboxylic acid imides and 1,4-naphtoquinone. Series of novel thiopyrano[2,3-d]thiazoles with low molecular weight were obtained.

5-Ethoxymethylidene-4-thioxo-2-thiazolidones with acethylenedicarboxylic acid, its dimethyl ester, aroylacrylic acids and 1,4-naphtoquinone [4+2]-cycloaddition adducts undergo spontaneous transformations, which include not only ethanol elimination, but also decarboxylation and regrouping of conjugated double bonds system depending on type of dienophile.

New variant of “domino”-reaction was proposed based on interaction of 5-(2-oxyphenylmethylidene)isorhodanines with acrolein (heterodiene synthesis / half-acetal formation), which allowed to obtain 6-hydroxy-3,5a,6,11b-tetrahydro-2Н,5Н-cromeno[4',3':4,5]thiopyrano [2,3-d]thiazol-2-ones.

Chemical transformations of 9,9-R¹,R²-3,7-dithia-5-azatetracyclo[9.2.1.0 ^2,10.0^4,8]tetradecen-4(8)-ones-6 was realized via N-alkylation by means of arylchloroacetamides and ethylchloroacetate with following hydrazinolysis and hydrazide transformations. 2-Oxo-7-(4-methoxyphenyl)-3,5,6,7-tetrahydro-2Н-thiopyrano[2,3-d]thiazol-6-carbaldehyde was functionalized into thiosemicarbazido-derivatives using an aldehyde group.

2-(2,6-Dioxo-3,5а,6,11b-tetrahydro-2Н,5Н-cromeno[4',3':4,5]thiopyrano[2,3-d]thiazol-5а-yl)acetic acids with amino-derivatives in reflux in acetic acid undergo recyclization yielding 7'-(2-hydroxyphenyl)-3',7'-dihydro-2H,2'H,5H-spiro[pyrolidin-3,6'-thiopyrano[2,3-d]thiazol]-2,2',5-triones. Amides row of 2,6-dioxo-3,5а,6,11b-tetrahydro-2Н,5Н-cromeno[4',3':4,5]thiopyrano[2,3-d]thiazol-substituted carboxylic acids were obtained using soft acylation reagent DCC.

Complex screening and “structure-activity” correlation studies allowed identication of 34 highly-active compounds with anticancer (11), antimycobacterial (6), antioxidant (8), antihypoxic (2), anticonvulsant (4), gastroprotectant (1) and antiviral (1) activities for advanced studies. Conciderable anticancer potential of polycyclic thiopyrano[2,3-d]thiazoles was identified, which possess high antimitotic effect at 60 human tumor cell lines with relative specificity to leukemia, melanoma and breast cancer, which allowed to propose eleven «lead-compounds» for advanced pharmacological studies. Computer-based COMPARE analysis, combined with docking studies and QSAR-analysis allowed to propose hypothesis about tubulin and protein-protein complex Bcl-X_L/ВН3, as biological molecular targets of anticancer activity for thiopyrano[2,3-d]thiazoles. Experimental lipophilicity was determined by reversed-phase thin-layer chromatography. Obtained Rm₀ values correlated well with LogP predicted values by ACD Labs and ChemOffice software.

9-(3-Ethoxy-4-oxyphenyl)-14-(4-fluorophenyl)-3,7-dithia-5,14-diazapentacyclo-[9.5.1.0^2,10.0^4,8.0^12,16]heptadecen-4(8)-trione was identified as a compound having the highest level of antioxidant and antihypoxic activities.

Antimycobacterial screening showed the high activity of 3,5,10,11-tetrahydro-2H-benzo[6,7]thiochromeno[2,3-d]thiazol-2,5,10-triones (MIC₉₀=0.677ч2.654 мg/ml), which however possess also certain cytotoxicity on VERO mammal cells and this limits their future development.

2-Oxo-7-(4-methoxyphenyl)-3,5,6,7-tetrahydro-2Н-thiopyrano[2,3-d]thiazol-6-carbaldehyde was selected in antiviral activity screening showing considerable activity against herpes-viruses group (HSV-1, EBV, VZV) with high selectivity indexes.

Keywords: synthesis, polycyclic fused thiazolidones, thiopyrano[2,3-d]thiazoles, spectral data, pharmacological studies, QSAR-analysis, docking, lipophilicity.