New Polyenes from the Marine-Derived Fungus Talaromyces cyanescens with Anti-Neuroinflammatory and Cytotoxic Activities

Three new polyene compounds, talacyanols A–C (1–3), along with two known compounds, ramulosin (4) and eurothiocin A (5), were isolated from the marine fungus Talaromyces cyanescens derived from a seaweed Caulerpa sp. Structures of 1–5 were established by one-dimensional and two-dimensional (1D/2D) NMR, HR-ESIMS, and the modified Mosher’s methods, as well as comparison with previously reported literature data. All the compounds (1–5) were tested for their in vitro cytotoxic and anti-neuroinflammatory activities. Among them, 1 showed moderate cytotoxic activity against a panel of cancer cell lines (HCT-15, NUGC-3, NCI-H23, ACHN, PC-3, and MDA-MB-231) with GI₅₀ values ranging from 44.4 to 91.6 μM, whereas compounds 2 and 5 exhibited anti-neuroinflammatory effect without cytotoxicity against all the tested cell lines.     

New Cu+2 Complexes with N-Sulfonamide Ligands: Potential Antitumor,Antibacterial, and Antioxidant Agents

Nowadays, the discovery of a new non-toxic metal complex with biological activity represents a very active area of research. Two Cu⁺² complexes, [Cu(L1)₂(H₂O)₃] (C1) (HL1= N-(5-(4-methylphenyl)-[1,3,4]–thiadiazole–2-yl)-naphtalenesulfonamide) and [Cu(L2)₂(py)₂(H₂O)] (C2) (HL2= N-(5-ethyl-[1,3,4]–thiadiazole–2-yl)-naphtalenesulfonamide), with two new ligands were synthesized. The X-ray crystal structures of the complexes were determined. In both complexes, Cu⁺² is five-coordinated, forming a CuN₂O₃ and CuN₄O chromophore, respectively. The ligands act as monodentate, coordinating the metal ion through a single N_thiadiazole atom; for the C2 complex, the molecules from the reaction medium (pyridine and water) are also involved in the coordination of Cu⁺². The complexes have a distorted square pyramidal square-planar geometry. The compounds were characterized by FT-IR, electronic EPR spectroscopy, and magnetic methods. The nuclease activity studies confirm the complexes’ capacity to cleave the DNA molecule. Using a xanthine-xanthine oxydase system, the SOD mimetic activity of the complexes was demonstrated. Cytotoxicity studies were carried out on two tumor cell lines (HeLa, WM35) and on a normal cell line (HFL1) using the MTT method, with cisplatin used as a positive control. The antibacterial activity of the complexes was investigated against two Gram-positive and two Gram-negative bacteria, and compared with Amoxicillin and Norfloxacin using the disk diffusion method. Both complexes showed in vitro biological activity but the C2 complex was more active. A lack of in vivo toxicity was demonstrated for the C2 complex by performing hepatic, renal, and hematological studies on Swiss mice.     

Design,Synthesis, Biological Evaluation,and Computational Studies of Novel Tri-Aryl Imidazole-Benzene Sulfonamide Hybrids as Promising Selective Carbonic Anhydrase IX and XII Inhibitors

A novel series of tri-aryl imidazole derivatives 5a–n carrying benzene sulfonamide moiety has been designed for their selective inhibitory against hCA IX and XII activity. Six compounds were found to be potent and selective CA IX inhibitors with the order of 5g > 5b > 5d > 5e > 5g > 5n (Ki = 0.3–1.3 μM, and selectivity ratio for hCA IX over hCA XII = 5–12) relative to acetazolamide (Ki = 0.03 μM, and selectivity ratio for hCA IX over hCA XII = 0.20). The previous sixth inhibitors have been further investigated for their anti-proliferative activity against four different cancer cell lines using MTT assay. Compounds 5g and 5b demonstrated higher antiproliferative activity than other tested compounds (with GI₅₀ = 2.3 and 2.8 M, respectively) in comparison to doxorubicin (GI₅₀ = 1.1 M). Docking studies of these two compounds adopted orientation and binding interactions with a higher liability to enter the active side pocket CA-IX selectively similar to that of ligand 9FK. Molecular modelling simulation showed good agreement with the acquired biological evaluation.     

Investigations on Anticancer Potentials by DNA Binding and Cytotoxicity Studies for Newly Synthesized and Characterized Imidazolidine and Thiazolidine-Based Isatin Derivatives

Imidazolidine and thiazolidine-based isatin derivatives (IST-01–04) were synthesized, characterized, and tested for their interactions with ds-DNA. Theoretical and experimental findings showed good compatibility and indicated compound–DNA binding by mixed mode of interactions. The evaluated binding parameters, i.e., binding constant (K_b), free energy change (ΔG), and binding site sizes (n), inferred comparatively greater and more spontaneous binding interactions of IST-02 and then IST-04 with the DNA, among all compounds tested under physiological pH and temperature (7.4, 37 °C). The cytotoxic activity of all compounds was assessed against HeLa (cervical carcinoma), MCF-7 (breast carcinoma), and HuH-7 (liver carcinoma), as well as normal HEK-293 (human embryonic kidney) cell lines. Among all compounds, IST-02 and 04 were found to be cytotoxic against HuH-7 cell lines with percentage cell toxicity of 75% and 66%, respectively, at 500 ng/µL dosage. Moreover, HEK-293 cells exhibit tolerance to the increasing drug concentration, suggesting these two compounds are less cytotoxic against normal cell lines compared to cancer cell lines. Hence, both DNA binding and cytotoxicity studies proved imidazolidine (IST-02) and thiazolidine (IST-04)-based isatin derivatives as potent anticancer drug candidates among which imidazolidine (IST-02) is comparatively the more promising.     

Two New Isoprenoid Flavonoids from Sophora flavescens with Antioxidant and Cytotoxic Activities

Sophora flavescens is a regularly used traditional Chinese medicine. In an attempt to discover adequate active agents, the isoprenoid flavonoids from S. flavescens were further investigated. In this work, two new compounds (1–2, kurarinol A-B) together with 26 known ones (3–28) were isolated and elucidated on the basis of extensive NMR, UV and MS analyses. Furthermore, the antioxidant activity of all constituents was assessed through ABTS, PTIO and DPPH methodologies and also were evaluated for cytotoxic activity by three tumor cell lines (HepG2, A549 and MCF7) and one human normal cell line (LO2 cells). As a result, a multitude of components revealed significant inhibitory activity. In particular, compound 1–2 (kurarinol A-B), two new flavanonols derivatives, exhibited the most potent ABTS inhibitory activity with IC₅₀ of 1.21 µg/mL and 1.81 µg/mL, respectively. Meanwhile, the new compound 1 demonstrated remarkable cytotoxicity against three cancer cells lines with IC₅₀ values ranging from 7.50–10.55 μM but showed little effect on the normal cell. The two new isoprenoid flavonoids could be promising antioxidant and anti-tumor nature agents.     

Novel Nitric Oxide Donor Dinitroazetidine-Coumarin Hybrids as Potent Anti-Intrahepatic Cholangiocarcinoma Agents

Intrahepatic cholangiocarcinoma (iCC) is a serious liver cancer threatening human health. However, there are a few chemotherapeutic drugs for the treatment of iCC in the clinic. It is extremely urgent to develop new drugs for iCC. In this study, twenty dinitroazetidine and coumarin hybrids were synthesized and evaluated anti-iCC bioactivity as a new type of nitric oxide (NO) donors. Among them, compounds 2–5 and 21 showed a higher antiproliferative activity against RBE cell lines (human intrahepatic cholangiocarcinoma cell lines) and low cytotoxicity in nontumor cells (HOSEpiC and T29). The preliminary study of pharmacology mechanism indicated that compounds 2–5 and 21 could release effective concentration of NO in RBE cell lines, which leaded to inhibit the proliferation of RBE cell lines. The research results revealed that compound 3 inhibited the proliferation of RBE cell lines by inducing apoptosis and arresting cell cycle at G₂/M phase. Additionally, compound 3 had acceptable metabolic stability. Therefore, compound 3 was merited to further explore for developing a desirable NO donor lead with anti-iCC activity.     

Facile One-Pot Multicomponent Synthesis of Pyrazolo-Thiazole Substituted Pyridines with Potential Anti-Proliferative Activity: Synthesis,In Vitro and In Silico Studies

Pyrazolothiazole-substituted pyridine conjugates are an important class of heterocyclic compounds with an extensive variety of potential applications in the medicinal and pharmacological arenas. Therefore, herein, we describe an efficient and facile approach for the synthesis of novel pyrazolo-thiazolo-pyridine conjugate 4, via multicomponent condensation. The latter compound was utilized as a base for the synthesis of two series of 15 novel pyrazolothiazole-based pyridine conjugates (5–16). The newly synthesized compounds were fully characterized using several spectroscopic methods (IR, NMR and MS) and elemental analyses. The anti-proliferative impact of the new synthesized compounds 5–13 and 16 was in vitro appraised towards three human cancer cell lines: human cervix (HeLa), human lung (NCI-H460) and human prostate (PC-3). Our outcomes regarding the anti-proliferative activities disclosed that all the tested compounds exhibited cytotoxic potential towards all the tested cell lines with IC₅₀ = 17.50–61.05 µM, especially the naphthyridine derivative 7, which exhibited the most cytotoxic potential towards the tested cell lines (IC₅₀ = 14.62–17.50 µM) compared with the etoposide (IC50 = 13.34–17.15 µM). Moreover, an in silico docking simulation study was performed on the newly prepared compounds within topoisomerase II (3QX3), to suggest the binding mode of these compounds as anticancer candidates. The in silico docking results indicate that compound 7 was a promising lead anticancer compound which possesses high binding affinity toward topoisomerase II (3QX3) protein.     

Triterpenes and Phenolic Compounds from the Fungus Fuscoporia torulosa: Isolation,Structure Determination and Biological Activity

Investigation of the methanol extract of the poroid fungus Fuscoporia torulosa resulted in the isolation of a novel triterpene, fuscoporic acid (1), together with inoscavin A and its previously undescribed Z isomer (2 and 3), 3,4-dihydroxy-benzaldehide (4), osmundacetone (5), senexdiolic acid (6), natalic acid (7), and ergosta-7,22-diene-3-one (8). The structures of fungal compounds were determined on the basis of NMR and MS spectroscopic analyses, as well as molecular modeling studies. Compounds 1, 6–8 were examined for their antibacterial properties on resistant clinical isolates, and cytotoxic activity on human colon adenocarcinoma cell lines. Compound 8 was effective against Colo 205 (IC₅₀ 11.65 ± 1.67 µM), Colo 320 (IC₅₀ 8.43 ± 1.1 µM) and MRC-5 (IC₅₀ 7.92 ± 1.42 µM) cell lines. Potentially synergistic relationship was investigated between 8 and doxorubicin, which revealed a synergism between the examined compounds with a combination index (CI) at the 50% growth inhibition dose (ED₅₀) of 0.521 ± 0.15. Several compounds (1 and 6–8) were tested for P-glycoprotein modulatory effect in Colo 320 resistant cancer cells, but none of the compounds proved to be effective in this assay. Fungal metabolites 2–5 were evaluated for their antioxidant activity using the oxygen radical absorbance capacity (ORAC) and DPPH assays. Compounds 4 and 5 were found to have a considerable antioxidant effect with EC₅₀ 0.25 ± 0.01 (DPPH) and 12.20 ± 0.92 mmol TE/g (ORAC). The current article provides valuable information on both the chemical and pharmacological profiles of Fuscoporia torulosa, paving the way for future studies with this species.     

Identification of Anti-Proliferative Compounds from Genista monspessulana Seeds through Covariate-Based Integration of Chemical Fingerprints and Bioactivity Datasets

Genista monspessulana (L.) L.A.S. Johnson (Fabaceae) is a Mediterranean plant introduced to South America and other regions for ornamental purposes. However, it is considered an invasive shrub due to its reproductive vigor in many areas. Unlike other Genista plants, G. monspessulana has few studies disclosing its biologically active components, particularly cytotoxic agents against cancer cells. Thus, as part of our research on anti-proliferative bioactives, a set of ethanolic seed extracts from ten accessions of G. monspessulana, collected in the Bogotá plateau, were evaluated against four cell lines: PC-3 (prostate adenocarcinoma), SiHa (cervical carcinoma), A549 (lung carcinoma), and L929 (normal mouse fibroblasts). Extracts were also analyzed through liquid chromatography coupled with mass spectrometry (LC/MS) to record chemical fingerprints and determine the composition and metabolite variability between accessions. Using multiple covariate statistics, chemical and bioactivity datasets were integrated to recognize patterns and identify bioactive compounds among studied extracts. G. monspessulana seed-derived extracts exhibited dose-dependent antiproliferative activity on PC-3 and SiHa cell lines (>500 µg/mL < IC₅₀ < 26.3 µg/mL). Seven compounds (1–7) were inferred as the compounds most likely responsible for the observed anti-proliferative activity and subsequently isolated and identified by spectroscopic techniques. A tricyclic quinolizidine (1) and a pyranoisoflavone (2) were found to be the most active compounds, exhibiting selectivity against PC-3 cell lines (IC₅₀ < 18.6 µM). These compounds were used as precursors to obtain a quinolizidine-pyranoisoflavone adduct via Betti reaction, improving the activity against PC-3 and comparable to curcumin as the positive control. Results indicated that this composition–activity associative approach is advantageous to finding those bioactive principles efficiently within active extracts. This correlative association can be employed in further studies focused on the targeted isolation of anti-proliferative compounds from Genista plants and accessions.     

Thiazole–Chalcone Hybrids as Prospective Antitubercular and Antiproliferative Agents: Design,Synthesis, Biological,Molecular Docking Studies and In Silico ADME Evaluation

Compounds bearing thiazole and chalcone pharmacophores have been reported to possess excellent antitubercular and anticancer activities. In view of this, we designed, synthesized and characterized a novel series of thiazole–chalcone hybrids (1–20) and further evaluated them for antitubercular and antiproliferative activities by employing standard protocols. Among the twenty compounds, chalcones 12 and 7, containing 2,4-difluorophenyl and 2,4-dichlorophenyl groups, showed potential antitubercular activity higher than the standard pyrazinamide (MIC = 25.34 µM) with MICs of 2.43 and 4.41 µM, respectively. Chalcone 20 containing heteroaryl 2-thiazolyl moiety exhibited promising antiproliferative activity against the prostate cancer cell line (DU-145), higher than the standard methotrexate (IC₅₀ = 11 ± 1 µM) with an IC₅₀ value of 6.86 ± 1 µM. Furthermore, cytotoxicity studies of these compounds against normal human liver cell lines (L02) revealed that the target molecules were comparatively less selective against L02. Additional computational studies using AutoDock predicted the key binding interactions responsible for the activity and the SwissADME tool computed the in silico drug likeliness properties. The lead compounds generated through this study, create a way for the optimization and development of novel drugs against tuberculosis infections and prostate cancer.     

Heterometallic titanium–gold complexes inhibit renal cancer cells in vitro and in vivo

Following recent work on heterometallic titanocene–gold complexes as potential chemotherapeutics for renal cancer, we report here on the synthesis, characterization and stability studies of new titanocene complexes containing a methyl group and a carboxylate ligand (mba = S–C₆H₄–COO^–) bound to gold(i)-phosphane fragments through a thiolate group [(η-C₅H₅)₂TiMe(μ-mba)Au(PR₃)]. The compounds are more stable in physiological media than those previously reported and are highly cytotoxic against human cancer renal cell lines. We describe here preliminary mechanistic data involving studies on the interaction of selected compounds with plasmid (pBR322) DNA used as a model nucleic acid, and with selected protein kinases from a panel of 35 protein kinases having oncological interest. Preliminary mechanistic studies in Caki-1 renal cells indicate that the cytotoxic and anti-migration effects of the most active compound 5 [(η-C₅H₅)₂TiMe(μ-mba)Au(PPh₃)] involve inhibition of thioredoxin reductase and loss of expression of protein kinases that drive cell migration (AKT, p90-RSK, and MAPKAPK3). The co-localization of both titanium and gold metals (1 : 1 ratio) in Caki-1 renal cells was demonstrated for 5 indicating the robustness of the heterometallic compound in vitro. Two compounds were selected for further in vivo studies on mice based on their selectivity in vitro against renal cancer cell lines when compared to non-tumorigenic human kidney cell lines (HEK-293T and RPTC) and the favourable preliminary toxicity profile in C57BL/6 mice. Evaluation of Caki-1 xenografts in NOD.CB17-Prkdc SCID/J mice showed an impressive tumor reduction (67%) after treatment for 28 days (3 mg per kg per every other day) with heterometallic compound 5 as compared with the previously described [(η-C₅H₅)₂Ti{OC(O)-4-C₆H₄-P(Ph₂)AuCl}₂] 3 which was non-inhibitory. These findings indicate that structural modifications on the ligand scaffold affect the in vivo efficacy of this class of compounds.     

Greener Synthesis of Antiproliferative Furoxans via Multicomponent Reactions

Prostate and bladder cancers are commonly diagnosed malignancies in men. Several nitric oxide donor compounds with strong antitumor activity have been reported. Thus, continuing with our efforts to explore the chemical space around bioactive furoxan moiety, multicomponent reactions were employed for the rapid generation of molecular diversity and complexity. We herein report the use of Ugi and Groebke–Blackburn–Bienaymé multicomponent reactions under efficient, safe, and environmentally friendly conditions to synthesize a small collection of nitric-oxide-releasing molecules. The in vitro antiproliferative activity of the synthesized compounds was measured against two different human cancer cell lines, LNCaP (prostate) and T24 (bladder). Almost all compounds displayed antiproliferative activity against both cancer cell lines, providing lead compounds with nanomolar GI₅₀ values against the cancer bladder cell line with selectivity indices higher than 10.     

Design,Synthesis, Molecular Modeling and Antitumor Evaluation of Novel Indolyl-Pyrimidine Derivatives with EGFR Inhibitory Activity

Scaffolds hybridization is a well-known drug design strategy for antitumor agents. Herein, series of novel indolyl-pyrimidine hybrids were synthesized and evaluated in vitro and in vivo for their antitumor activity. The in vitro antiproliferative activity of all compounds was obtained against MCF-7, HepG2, and HCT-116 cancer cell lines, as well as against WI38 normal cells using the resazurin assay. Compounds 1–4 showed broad spectrum cytotoxic activity against all these cancer cell lines compared to normal cells. Compound 4g showed potent antiproliferative activity against these cell lines (IC₅₀ = 5.1, 5.02, and 6.6 μM, respectively) comparable to the standard treatment (5-FU and erlotinib). In addition, the most promising group of compounds was further evaluated for their in vivo antitumor efficacy against EAC tumor bearing mice. Notably, compound 4g showed the most potent in vivo antitumor activity. The most active compounds were evaluated for their EGFR inhibitory (range 53–79%) activity. Compound 4g was found to be the most active compound against EGFR (IC₅₀ = 0.25 µM) showing equipotency as the reference treatment (erlotinib). Molecular modeling study was performed on compound 4g revealed a proper binding of this compound inside the EGFR active site comparable to erlotinib. The data suggest that compound 4g could be used as a potential anticancer agent.     

Design,Synthesis, and Antitumor Activity of Olmutinib Derivatives Containing Acrylamide Moiety

Two series of olmutinib derivatives containing an acrylamide moiety were designed and synthesized, and their IC₅₀ values against cancer cell lines (A549, H1975, NCI-H460, LO2, and MCF-7) were evaluated. Most of the compounds exhibited moderate cytotoxic activity against the five cancer cell lines. The most promising compound, H10, showed not only excellent activity against EGFR kinase but also positive biological activity against PI3K kinase. The structure–activity relationship (SAR) suggested that the introduction of dimethylamine scaffolds with smaller spatial structures was more favorable for antitumor activity. Additionally, the substitution of different acrylamide side chains had different effects on the activity of compounds. Generally, compounds H7 and H10 were confirmed as promising antitumor agents.     

Synthesis and Biological Activity Evaluation of Coumarin-3-Carboxamide Derivatives

A series of novel coumarin-3-carboxamide derivatives were designed and synthesized to evaluate their biological activities. The compounds showed little to no activity against gram-positive and gram-negative bacteria but specifically showed potential to inhibit the growth of cancer cells. In particular, among the tested compounds, 4-fluoro and 2,5-difluoro benzamide derivatives (14b and 14e, respectively) were found to be the most potent derivatives against HepG2 cancer cell lines (IC₅₀ = 2.62–4.85 μM) and HeLa cancer cell lines (IC₅₀ = 0.39–0.75 μM). The activities of these two compounds were comparable to that of the positive control doxorubicin; especially, 4-flurobenzamide derivative (14b) exhibited low cytotoxic activity against LLC-MK2 normal cell lines, with IC₅₀ more than 100 μM. The molecular docking study of the synthesized compounds revealed the binding to the active site of the CK2 enzyme, indicating that the presence of the benzamide functionality is an important feature for anticancer activity.     

Design,Synthesis, Spectroscopic Characterisation and In Vitro Cytostatic Evaluation of Novel Bis(coumarin-1,2,3-triazolyl)benzenes and Hybrid Coumarin-1,2,3-triazolyl-aryl Derivatives

In this work, a series of novel 1,2,3-triazolyl-coumarin hybrid systems were designed as potential antitumour agents. The structural modification of the coumarin ring was carried out by Cu(I)-catalysed Huisgen 1,3-dipolar cycloaddition of 7-azido-4-methylcoumarin and terminal aromatic alkynes to obtain 1,4-disubstituted 1,2,3-triazolyl-coumarin conjugates 2a–g, bis(1,2,3-triazolyl-coumarin)benzenes 2h–i and coumarin-1,2,3-triazolyl-benzazole hybrids 4a–b. The newly synthesised hybrid molecules were investigated for in vitro antitumour activity against five human cancer cell lines, colon carcinoma HCT116, breast carcinoma MCF-7, lung carcinoma H 460, human T-lymphocyte cells CEM, cervix carcinoma cells HeLa, as well as human dermal microvascular endothelial cells (HMEC-1). Most of these compounds showed moderate to pronounced cytotoxic activity, especially towards MCF-7 cell lines with IC₅₀ = 0.3–32 μM. In addition, compounds 2a–i and 4a–b were studied by UV-Vis absorption and fluorescence spectroscopy and their basic photophysical parameters were determined.     

Novel Pyridothienopyrimidine Derivatives: Design,Synthesis and Biological Evaluation as Antimicrobial and Anticancer Agents

The growing risk of antimicrobial resistance besides the continuous increase in the number of cancer patients represents a great threat to global health, which requires intensified efforts to discover new bioactive compounds to use as antimicrobial and anticancer agents. Thus, a new set of pyridothienopyrimidine derivatives 2a,b–9a,b was synthesized via cyclization reactions of 3-amino-thieno[2,3-b]pyridine-2-carboxamides 1a,b with different reagents. All new compounds were evaluated against five bacterial and five fungal strains. Many of the target compounds showed significant antimicrobial activity. In addition, the new derivatives were further subjected to cytotoxicity evaluation against HepG-2 and MCF-7 cancer cell lines. The most potent cytotoxic candidates (3a, 4a, 5a, 6b, 8b and 9b) were examined as EGFR kinase inhibitors. Molecular docking study was also performed to explore the binding modes of these derivatives at the active site of EGFR-PK. Compounds 3a, 5a and 9b displayed broad spectrum antimicrobial activity with MIC ranges of 4–16 µg/mL and potent cytotoxic activity with IC₅₀ ranges of 1.17–2.79 µM. In addition, they provided suppressing activity against EGFR with IC₅₀ ranges of 7.27–17.29 nM, higher than that of erlotinib, IC₅₀ = 27.01 nM.     

Macrooxazoles A–D,New 2,5-Disubstituted Oxazole-4-Carboxylic Acid Derivatives from the Plant Pathogenic Fungus Phoma macrostoma

In our ongoing search for new bioactive fungal metabolites, four previously undescribed oxazole carboxylic acid derivatives (1–4) for which we proposed the trivial names macrooxazoles A–D together with two known tetramic acids (5–6) were isolated from the plant pathogenic fungus Phoma macrostoma. Their structures were elucidated based on high-resolution mass spectrometry (HR-MS) and nuclear magnetic resonance (NMR) spectroscopy. The hitherto unclear structure of macrocidin Z (6) was also confirmed by its first total synthesis. The isolated compounds were evaluated for their antimicrobial activities against a panel of bacteria and fungi. Cytotoxic and anti-biofilm activities of the isolates are also reported herein. The new compound 3 exhibited weak-to-moderate antimicrobial activity as well as the known macrocidins 5 and 6. Only the mixture of compounds 2 and 4 (ratio 1:2) showed weak cytotoxic activity against the tested cancer cell lines with an IC₅₀ of 23 µg/mL. Moreover, the new compounds 2 and 3, as well as the known compounds 5 and 6, interfered with the biofilm formation of Staphylococcus aureus, inhibiting 65%, 75%, 79%, and 76% of biofilm at 250 µg/mL, respectively. Compounds 5 and 6 also exhibited moderate activity against S. aureus preformed biofilm with the highest inhibition percentage of 75% and 73% at 250 µg/mL, respectively.     

Evaluation of Neurotropic Activity and Molecular Docking Study of New Derivatives of pyrano[4″,3″:4′,5′]pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidines on the Basis of pyrano[3,4-c]pyridines

Background: Heterocyclic compounds and their fused analogs, which contain pharmacophore fragments such as pyridine, thiophene and pyrimidine rings, are of great interest due to their broad spectrum of biological activity. Chemical compounds containing two or more pharmacophore groups due to additional interactions with active receptor centers usually enhance biological activity and can even lead to a new type of activity. The search for new effective neurotropic drugs in the series of derivatives of heterocycles containing pharmacophore groups in organic, bioorganic and medical chemistry is a serious problem. Methods: Modern methodology of drugs involves synthesis, physicochemical study, molecular modeling and selection of active compounds through virtual screening and experimental evaluation of the biological activity of new chimeric compounds with pharmacophore fragments. For the synthesis of new compounds, classical organic methods were used and developed. For the evaluation of neurotropic activity of new synthesized compounds, some biological methods were used according to indicators characterizing anticonvulsant, sedative and antianxiety activity as well as side effects. For docking analysis, various soft ware packages and methods were used. Results: As a result of multistep reactions, 11 new, tri- and tetracyclic heterocyclic systems were obtained. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures as well as some psychotropic effects. The biological assays evidenced that nine of the eleven studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of the compounds is low, and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity, it was found that the selected compounds have an activating behavior and anxiolytic effects on the “open field” and “elevated plus maze” (EPM) models. The data obtained indicate the anxiolytic (antianxiety) activity of the derivatives of tricyclic thieno[2,3-b]pyridines and tetracyclic pyridothieno[3,2-d]pyrimidin-8-ones, especially pronounced in compounds 3b–f and 4e. The studied compounds increase the latent time of first immobilization on the “forced swimming” (FS) model and exhibit antidepressant effects; compounds 3e and 3f especially exhibit these effects, similarly to diazepam. Docking studies revealed that compounds 3c and 4b bound tightly in the active site of γ-aminobutyric acid type A (GABA_A) receptors with a value of the scoring function that estimates free energy of binding (∆G) at −10.0 ± 5 kcal/mol. Compound 4e showed the best affinity ((∆G) at −11.0 ± 0.54 kcal/mol) and seems to be an inhibitor of serotonin (SERT) transporter. Compounds 3c–f and 4e practically bound with the groove of T4L of 5HT_1A and blocked it completely, while the best affinity observed was in compound 3f ((∆G) at −9.3 ± 0.46 kcal/mol). Conclusions: The selected compounds have an anticonvulsant, activating behavior and anxiolytic effects and at the same time exhibit antidepressant effects.     

New Analogs of Polyamine Toxins from Spiders and Wasps: Liquid Phase Fragment Synthesis and Evaluation of Antiproliferative Activity

Polyamine toxins (PATs) are conjugates of polyamines (PAs) with lipophilic carboxylic acids, which have been recently shown to present antiproliferative activity. Ten analogs of the spider PATs Agel 416, HO-416b, and JSTX-3 and the wasp PAT PhTX-433 were synthesized with changes in the lipophilic head group and/or the PA chain, and their antiproliferative activity was evaluated on MCF-7 and MDA-MB-231 breast cancer cells, using Agel 416 and HO-416b as reference compounds. All five analogs of PhTX-433 were of very low activity on both cell lines, whereas the two analogs of JSTX-3 were highly active only on the MCF-7 cell line with IC₅₀ values of 2.63–2.81 μΜ. Of the remaining three Agel 416 or HO-416b analogs, only the one with the spermidine chain was highly active on both cells with IC₅₀ values of 3.15–12.6 μM. The two most potent compounds in this series, Agel 416 and HO-416b, with IC₅₀ values of 0.09–3.98 μΜ for both cell lines, were found to have a very weak cytotoxic effect on the MCF-12A normal breast cells. The present study points out that the structure of both the head group and the PA chain determine the strength of the antiproliferative activity of PATs and their selectivity towards different cells.