X-ray Structures and Computational Studies of Two Bioactive 2-(Adamantane-1-carbonyl)-N-substituted Hydrazine-1-carbothioamides.

Two biologically active adamantane-linked hydrazine-1-carbothioamide derivatives, namely 2-(adamantane-1-carbonyl)-N-(tert-butyl)hydrazine-1-carbothioamide) 1 and 2-(adamantane-1-carbonyl)-N-cyclohexylhydrazine-1-carbothioamide 2, have been synthesized. X-ray analysis was conducted to study the effect of the t-butyl and cyclohexyl moieties on the intermolecular interactions and conformation of the molecules in the solid state. X-ray analysis reveals that compound 1 exhibits folded conformation, whereas compound 2 adopts extended conformation. The Hirshfeld surface analysis indicates that the contributions of the major intercontacts involved in the stabilization of the crystal structures do not change much as a result of the t-butyl and cyclohexyl moieties. However, the presence and absence of these contacts is revealed by the 2D-fingerprint plots. The CLP-Pixel method was used to identify the energetically significant molecular dimers. These dimers are stabilized by different types of intermolecular interactions such as N-H···S, N-H···O, C-H···S, C-H···O, H-H bonding and C-H···π interactions. The strength of these interactions was quantified by using the QTAIM approach. The results suggest that N-H···O interaction is found to be stronger among other interactions. The in vitro assay suggests that both compounds 1 and 2 exhibit urease inhibition potential, and these compounds also display moderate antiproliferative activities. Molecular docking analysis shows the key interaction between urease enzyme and title compounds.

1,3,4-Oxadiazole N-Mannich Bases: Synthesis, Antimicrobial, and Anti-Proliferative Activities.

The reaction of 5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thione 3 with formaldehyde solution and primary aromatic amines or 1-substituted piperazines, in ethanol at room temperature yielded the corresponding N-Mannich bases 3-arylaminomethyl-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones 4a-l or 3-[(4-substituted piperazin-1-yl)methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones 5a-d, respectively. The in vitro inhibitory activity of compounds 4a-l and 5a-d was assessed against pathogenic Gram-positive, Gram-negative bacteria, and the yeast-like pathogenic fungus Candida albicans. The piperazinomethyl derivatives 5c and 5d displayed broad-spectrum antibacterial activities the minimal inhibitory concentration (MIC) 0.5-8 µg/mL) and compounds 4j, 4l, 5a, and 5b showed potent activity against the tested Gram-positive bacteria. In addition, the anti-proliferative activity of the compounds was evaluated against prostate cancer (PC3), human colorectal cancer (HCT-116), human hepatocellular carcinoma (HePG-2), human epithelioid carcinoma (HeLa), and human breast cancer (MCF7) cell lines. The optimum anti-proliferative activity was attained by compounds 4l, 5a, 5c, and 5d.

Synthesis, Antimicrobial, and Anti-Proliferative Activities of Novel 4-(Adamantan-1-yl)-1-arylidene-3-thiosemicarbazides, 4-Arylmethyl N'-(Adamantan-1-yl)piperidine-1-carbothioimidates, and Related Derivatives.

The reaction of 4-(adamantan-1-yl)-3-thiosemicarbazide 3 with various aromatic aldehydes yielded the corresponding thiosemicarbazones 4a-g. 1-Adamantyl isothiocyanate 2 was reacted with 1-methylpiperazine or piperidine to yield the corresponding N-(adamantan-1-yl)carbothioamides 5 and 6, respectively. The latter was reacted with benzyl or substituted benzyl bromides to yield the S-arylmethyl derivatives 7a-c. Attempted cyclization of 1,3-bis(adamantan-1-yl)thiourea 8 with chloroacetic acid via prolonged heating to the corresponding thiazolidin-4-one 9 resulted in desulfurization of 8 to yield its urea analogue 10. The thiazolidin-4-one 9 and its 5-arylidene derivatives 11a,b were obtained via microwave-assisted synthesis. The in vitro antimicrobial activity of the synthesized compounds was evaluated against a panel of Gram-positive and Gram-negative bacteria and yeast-like pathogenic fungus Candida albicans. Compounds 7a-c displayed marked broad spectrum antibacterial activities (minimal inhibitory concentration (MIC), 0.5-32 µg/mL) and compounds 4a and 4g showed good activity against Candida albicans. Nine representative compounds were evaluated for anti-proliferative activity towards three human tumor cell lines. Compounds 7a-c displayed significant generalized anti-proliferative activity against all the tested cell lines with IC50 < 10 µM.

Adamantane-Isothiourea Hybrid Derivatives: Synthesis, Characterization, In Vitro Antimicrobial, and In Vivo Hypoglycemic Activities.

A new series of adamantane-isothiourea hybrid derivatives, namely 4-arylmethyl (Z)-N'-(adamantan-1-yl)-morpholine-4-carbothioimidates 7a-e and 4-arylmethyl (Z)-N'-(adamantan-1-yl)-4-phenylpiperazine-1-carbothioimidates 8a-e were prepared via the reaction of N-(adamantan-1-yl)morpholine-4-carbothioamide 5 and N-(adamantan-1-yl)-4-phenylpiperazine-1-carbothioamide 6 with benzyl or substituted benzyl bromides, in acetone, in the presence of anhydrous potassium carbonate. The structures of the synthesized compounds were confirmed by ¹H-NMR, 13C-NMR, electrospray ionization mass spectral (ESI-MS) data, and X-ray crystallographic data. The in vitro antimicrobial activity of the new compounds was determined against certain standard strains of pathogenic bacteria and the yeast-like pathogenic fungus Candida albicans. Compounds 7b, 7d and 7e displayed potent broad-spectrum antibacterial activity, while compounds 7a, 7c, 8b, 8d and 8e were active against the tested Gram-positive bacteria. The in vivo oral hypoglycemic activity of the new compounds was carried on streptozotocin (STZ)-induced diabetic rats. Compounds 7a, 8ab, and 8b produced potent dose-independent reduction of serum glucose levels, compared to the potent hypoglycemic drug gliclazide.

Synthesis, Antimicrobial and Hypoglycemic Activities of Novel N-(1-Adamantyl)carbothioamide Derivatives.

The reaction of 1-adamantyl isothiocyanate 4 with the various cyclic secondary amines yielded the corresponding N-(1-adamantyl)carbothioamides 5a-e, 6, 7, 8a-c and 9. Similarly, the reaction of 4 with piperazine and trans-2,5-dimethylpiperazine in 2:1 molar ratio yielded the corresponding N,N'-bis(1-adamantyl)piperazine-1,4-dicarbothioamides 10a and 10b, respectively. The reaction of N-(1-adamantyl)-4-ethoxycarbonylpiperidine-1-carbothioamide 8c with excess hydrazine hydrate yielded the target carbohydrazide 11, in addition to 4-(1-adamantyl)thiosemicarbazide 12 as a minor product. The reaction of the carbohydrazide 11 with methyl or phenyl isothiocyanate followed by heating in aqueous sodium hydroxide yielded the 1,2,4-triazole analogues 14a and 14b. The reaction of the carbohydrazide 11 with various aromatic aldehydes yielded the corresponding N'-arylideneamino derivatives 15a-g. The compounds 5a-e, 6, 7, 8a-c, 9, 10a, 10b, 14a, 14b and 15a-g were tested for in vitro antimicrobial activity against certain strains of pathogenic Gram-positive and Gram-negative bacteria and the yeast-like fungus Candida albicans. The compounds 5c, 5d, 5e, 6, 7, 10a, 10b, 15a, 15f and 15g showed potent antibacterial activity against one or more of the tested microorganisms. The oral hypoglycemic activity of compounds 5c, 6, 8b, 9, 14a and 15b was determined in streptozotocin (STZ)-induced diabetic rats. Compound 5c produced significant reduction of serum glucose levels, compared to gliclazide.

Antimicrobial and hypoglycemic activities of novel N-Mannich bases derived from 5-(1-adamantyl)-4-substituted-1,2,4-triazoline-3-thiones.

The reaction of 5-(1-adamantyl)-4-ethyl or allyl-1,2,4-triazoline-3-thione with formaldehyde solution and various 1-substituted piperazines yielded the corresponding N-Mannich bases. The newly synthesized N-Mannich bases were tested for in vitro inhibitory activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Six compounds showed potent antibacterial activity against one or more of the tested microorganisms, while two compounds exhibited moderate activity against the tested Gram-positive bacteria. None of the newly synthesized compounds were proved to possess marked activity against Candida albicans. The oral hypoglycemic activity of six compounds was determined in streptozotocin (STZ)-induced diabetic rats. Four compounds produced significant strong dose-dependent reduction of serum glucose levels, compared to gliclazide at 10 mg/kg dose level (potency ratio > 75%).

Evaluating anticancer activity of emodin by enhancing antioxidant activities and affecting PKC/ADAMTS4 pathway in thioacetamide-induced hepatocellular carcinoma in rats.

Emodin is a naturally occurring anthraquinone derivative with a wide range of pharmacological activities, including neuroprotective and anti-inflammatory activities. We aim to assess the anticancer activity of emodin against hepatocellular carcinoma (HCC) in rat models using the proliferation, invasion, and angiogenesis biomarkers. After induction of HCC, assessment of the liver impairment and the histopathology of liver sections were investigated. Hepatic expression of both mRNA and protein of the oxidative stress biomarkers, HO-1, Nrf2; the mitogenic activation biomarkers, ERK5, PKCδ; the tissue destruction biomarker, ADAMTS4; the tissue homeostasis biomarker, aggregan; the cellular fibrinolytic biomarker, MMP3; and of the cellular angiogenesis biomarker, VEGF were measured. Emodin increased the survival percentage and reduced the number of hepatic nodules compared to the HCC group. Besides, emodin reduced the elevated expression of both mRNA and proteins of all PKC, ERK5, ADAMTS4, MMP3, and VEGF compared with the HCC group. On the other hand, emodin increased the expression of mRNA and proteins of Nrf2, HO-1, and aggrecan compared with the HCC group. Therefore, emodin is a promising anticancer agent against HCC preventing the cancer prognosis and infiltration. It works through many mechanisms of action, such as blocking oxidative stress, proliferation, invasion, and angiogenesis.

Combined quercetin and simvastatin attenuate hepatic fibrosis in rats by modulating SphK1/NLRP3 pathways.

Liver fibrosis involves several signalling pathways working in concert regulating the deposition of extracellular matrix. In this study, we evaluated the effect of quercetin and simvastatin alone and their combination on the treatment of experimentally induced hepatic fibrosis in rats. To decipher the potential mechanisms involved, liver fibrosis was induced in rats by administration of 40 % carbon tetrachloride (CCl4) (1 µl/g rat, i.p., twice weekly) for 6 weeks. Quercetin (50 mg/kg, orally), simvastatin (40 mg/kg, orally) either individually or combined were administered for another 4 weeks. The three treatment groups ameliorated hepatic dysfunction and altered parameters of sphingolipid and pyroptosis pathways. Yet, the combined group showed a more pronounced effect. Treatments lowered serum levels of GOT, GPT, ALP and elevated albumin and total protein levels. Histopathological and electron microscope examination of liver tissue revealed diminished fibrosis and inflammation. Protein expression levels of α-SMA, IL-1ß, PPAR-γ, TGF-ß1, caspase-1 and caspase-3 expression in liver tissues were reduced. Additionally, hepatic mRNA levels of SphK1 and NLRP3 decreased after treatment. Furthermore, the three groups lowered MDA levels and elevated total antioxidant capacity, GSH and Nrf2 expression levels. Treatments downregulated sphingolipid pathway and NLRP3-mediated pyroptosis and stimulated an anti-apoptotic, anti-proliferative and antioxidant activity. This suggests that targeting the SphK1/NLRP3 pathway could be a prospective therapeutic strategy against liver fibrosis.

Echinacoside ameliorates hepatic fibrosis and tumor invasion in rats with thioacetamide-induced hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) affects approximately 800,000 individuals globally each year. Despite advancements in HCC treatments, there is still a pressing need to identify new drugs that can combat resistance. One potential option is echinacoside, a natural caffeic acid glycoside with antioxidant, anti-inflammatory, antidepressant, and antidiabetic properties. Therefore, we aimed to investigate the ability of echinacoside to exhibit antitumor activity against HCC in rats through ameliorating hepatic fibrosis and tumor invasion. Rats were given thioacetamide to induce HCC, and some were given 30 mg/kg of echinacoside twice a week for 16 weeks. The liver impairment was assessed by measuring serum α-fetoprotein (AFP) and examining liver sections stained with Masson trichrome or anti-transforming growth factor (TGF)-ß1 antibodies. The hepatic expression of mRNA and protein levels of TGF-ß1, ß-catenin, SMAD4, matrix metalloproteinase-9 (MMP9), phosphoinositide 3-kinases (PI3K), mammalian target of rapamycin (mTOR), connective tissue growth factor 2 (CCN2), E-Cadherin, platelets derived growth factor (PDGF)-B and fascin were also analyzed. Echinacoside improved the survival rate of rats by decreasing serum AFP and the number of hepatic nodules. Examination of micro-images indicated that echinacoside can reduce fibrosis. It also significantly decreased the expression of TGF-ß1, ß-catenin, SMAD4, MMP9, PI3K, mTOR, CCN2, PDGF-B, and fascin while enhancing the expression of E-Cadherin. In conclusion, echinacoside exhibits a protective effect against HCC by increasing survival rates and decreasing tumor growth. It also acts as an inhibitor of the hepatic tissue fibrosis pathway by reducing the expression of TGF-ß1, ß-catenin, SMAD4, PI3K, CCN2, PDGF-B and mTOR. Additionally, it prevents tumor invasion by suppressing MMP9 and fascin, and increasing the expression of E-Cadherin.

Role of Arctiin in Fibrosis and Apoptosis in Experimentally Induced Hepatocellular Carcinoma in Rats.

Background and objectives Hepatocellular carcinoma (HCC) is a highly aggressive malignant tumor with a poor prognosis. It is currently the second most common cause of cancer-related mortality. Arctiin, a compound found in plants commonly used as a vegetable in Asian countries and as an ingredient in traditional European dishes, possesses various properties, including anti-proliferative, anti-senescence, anti-oxidative, anti-tumor, toxic, anti-adipogenic, and anti-bacterial effects. Our study aims to investigate the potential antitumor activity of arctiin against HCC in rats by inhibiting cell fibrosis and apoptosis. Methods Rats were induced with HCC by administering thioacetamide. Arctiin was orally administered to some rats twice a week for 16 weeks at a dose of 30 mg/kg. The liver impairment was evaluated by measuring serum α-fetoprotein (AFP) and examining liver sections stained with Masson trichrome or anti-hypoxia-induced factor-1α (HIF-1α) antibodies. The hepatic expression of messenger RNA and protein levels of HIF-1α, protein kinase C (PKC), extracellular signal-regulated kinase (ERK), ß-catenin, and mothers against decapentaplegic homolog 4 (SMAD4) were analyzed. Results Our study demonstrated that arctiin can potentially increase the survival rate of rats. This is achieved through a reduction in serum AFP levels and hepatic nodules. We also observed that arctiin has the ability to inhibit the formation of fibrotic tissues and necrotic nodules in HCC rats. Additionally, arctiin can significantly decrease the expression of HIF-1α, PKC, ERK, ß-catenin, and SMAD4. Conclusion Arctiin has demonstrated potential anti-tumor properties that could ameliorate HCC. Studies have shown that it may increase survival rates and reduce the number of tumors and AFP levels. Arctiin works by inhibiting HCC-induced hypoxia, thus blocking the expression of HIF-1α. It also helps to slow down tumor fibrosis by decreasing the expression of ß-catenin and SMAD4. Furthermore, arctiin has been found to downregulate PKC and ERK, reducing hepatic tissue apoptosis.

Effects of Cycloastragenol on Alzheimer's Disease in Rats by Reducing Oxidative Stress, Inflammation, and Apoptosis.

BACKGROUND: As individuals age, they may develop Alzheimer's disease (AD), which is characterized by difficulties in speech, memory loss, and other issues related to neural function. Cycloastragenol is an active ingredient of Astragalus trojanus and has been used to treat inflammation, aging, heart disease, and cancer. OBJECTIVES: This study aimed to explore the potential therapeutic benefits of cycloastragenol in rats with experimentally induced AD. Moreover, the underlying molecular mechanisms were also evaluated by measuring Nrf2 and HO-1, which are involved in oxidative stress, NFκB and TNF-α, which are involved in inflammation, and BCL2, BAX, and caspase-3, which are involved in apoptosis. METHODS: Sprague-Dawley rats were given 70 mg/kg of aluminum chloride intraperitoneally daily for six weeks to induce AD. Following AD induction, the rats were given 25 mg/kg of cycloastragenol daily by oral gavage for three weeks. Hippocampal sections were stained with hematoxylin/ eosin and with anti-caspase-3 antibodies. The Nrf2, HO-1, NFκB, TNF-α, BCL2, BAX, and caspase-3 gene expressions and protein levels in the samples were analyzed. RESULTS: Cycloastragenol significantly improved rats' behavioral test performance. It also strengthened the organization of the hippocampus. Cycloastragenol significantly improved behavioral performance and improved hippocampal structure in rats. It caused a marked decrease in the expression of NFκB, TNF-α, BAX, and caspase-3, which was associated with an increase in the expression of BCL2, Nrf2, and HO-1. CONCLUSION: Cycloastragenol improved the structure of the hippocampus in rats with AD. It enhanced the outcomes of behavioral tests, decreased the concentration of AChE in the brain, and exerted antioxidant and anti-inflammatory effects. Antiapoptotic effects were also noted, leading to significant improvements in cognitive function, memory, and behavior in treated rats.

Novel Adamantane-Linked Isothiourea Derivatives as Potential Chemotherapeutic Agents: Synthesis, Structural Insights, and Antimicrobial/Anti-Proliferative Profiles.

In this study, two adamantane-linked isothiourea derivatives containing a common 4-chlorophenyl substituent coupled with 4-nitrobenzyl or 4-bromobenzyl moieties were synthesized. Both derivatives were characterized, in the solid state and in solution, through a synergistic combination of experimental and in silico techniques, and the results are of great value for the chemical and structural characterization of related compounds. The crystal structures of both derivatives were analyzed in depth, including Hirshfeld surface analysis and lattice energy calculations, revealing a predominant dispersive component of the total energy that stabilizes crystal packing. Both compounds showed potent broad-spectrum antibacterial activity and moderate activity against the pathogenic fungus Candida albicans. In addition, in vitro anti-proliferative activity assays showed that the 4-bromobenzyl analogue displays higher activity than the 4-nitrobenzyl one, with IC50 values under 30 µM against five human cancer cell lines. Our results give evidence of the potential of the adamantane/isothiourea combination to render auspicious scaffolds for new potential chemotherapeutic agents.

Garcinol-Attenuated Gastric Ulcer (GU) Experimentally Induced in Rats Via Affecting Inflammation, Cell Proliferation, and DNA Polymerization.

BACKGROUND:  Gastric ulcer (GU) is one of the most critical gastrointestinal tract disorders. Garcinol is a polyisoprenylated benzophenone in Garcinia fruit with antioxidant and anti-inflammatory priorities. OBJECTIVES:  We aimed to assess the protective effects of garcinol against GU induced in rats. We investigated garcinol's effects on DNA polymerization via mammalian targets of rapamycin (mTOR) and cyclin D1, cell proliferation via proliferating cell nuclear antigen (PCNA), inflammatory pathway via cyclooxygenase-2 (COX2), TNF-α, and IL-1ß, and anti-inflammatory pathway via IL-4 and IL10. METHODS:  In our study, we administered a single oral dose of 80 mg/kg of indomethacin to rats to induce GU. Some of the rats were given a treatment of 50 mg/kg of garcinol. We examined the expressions of mTOR, cyclin D1, PCNA, COX2, TNF-α, and IL-1ß/4/10 in the gastric tissues. Furthermore, we stained sections of the gastric tissues with Masson trichrome. RESULTS:  The areas of gastric tissues in the GU group showed severe hemorrhage and extensive fibrosis. Treating GU rats with garcinol prevented bleeding and ameliorated the fibrosis caused in gastric cells by GU. Moreover, treatment with garcinol significantly decreased the expression of mTOR, cyclin D1, PCNA, COX2, TNF-α, and IL-1ß associated with elevation of IL-4 and IL-10. CONCLUSION:  Garcinol has been found to provide therapeutic benefits in rats with induced GU. These benefits may be due to its ability to decrease the expression of DNA polymerization markers, cell proliferation markers, and inflammatory markers at the gene and protein levels.

Genistein ameliorated experimentally induced gastric ulcer in rats via inhibiting gastric tissues fibrosis by modulating Wnt/ß-catenin/TGF-ß/PKB pathway.

OBJECTIVES: Gastric ulcer (GU) is a prevalent chronic digestive disease affecting about 10% of the world's population leading to gastrointestinal perforation and bleeding. Genistein is a legume flavonoid with antioxidants, anti-inflammatory and antibacterial activities. Therefore, we aimed to investigate the ability of genistein to reduce experimentally induced GU in rats by affecting gastric tissue fibrosis Wnt/ß-catenin/TGF-ß/SMAD4 pathway. METHODS: Thirty rats were used. Ten rats served as control, and GU was induced in twenty rats using a single dose of indomethacin (80 mg/kg) orally. Following induction of GU, ten were treated with genistein 25 mg/kg orally. The gastric tissues were isolated to investigate markers of gastric fibrosis, Wnt, ß-catenin, transforming growth factor (TGF)-ß, SMAD4, and Protein kinase B (PKB). In addition, gastric sections were stained with PAS and anti-TGF-ß antibodies. RESULTS: Investigation GU micro-images revealed degeneration in both surface cells and glandular epithelial cells, which was improved by genistein. In addition, treatment with genistein significantly reduced the expression of Wnt, ß-catenin, TGF-ß, SMAD4, and PKB. CONCLUSION: Besides antioxidant activity, genistein improves experimentally induced GU in rats, at least in part, via reduction of gastric tissue fibrosis as indicated by reduction in expression of Wnt, ß-catenin, TGF-ß, SMAD4, and PKB.

Supramolecular Self-Assembly Mediated by Multiple Hydrogen Bonds and the Importance of C-S···N Chalcogen Bonds in N'-(Adamantan-2-ylidene)hydrazide Derivatives.

The present article comprehensively examines six N'-(adamantan-2-ylidene)hydrazide derivatives using the Hirshfeld surface analysis, PIXEL energy for molecular dimers, lattice energies for crystal packing, and topological analysis for intramolecular and intermolecular interactions. The crystal structure of one of the N'-(adamantan-2-ylidene)hydrazide derivatives, namely, N'-(adamantan-2-ylidene)-5-bromothiophene-2-carbohydrazide 1, C15H17N2OSBr, has been determined and analyzed in detail along with five closely related structures. The molecular conformation of 1 is locked by an intramolecular C-S···N chalcogen bond as found in one of its closely related structure, namely, N'-(adamantan-2-ylidene)thiophene-2-carbohydrazide. Furthermore, a detailed potential energy surface scan analysis has been performed to highlight the importance of a chalcogen bond. Two of these compounds possess syn-orientation for amide units, whereas the corresponding moiety exhibits anti-conformations in the remaining four structures. The Hirshfeld surface and its decomposed fingerprint plots provide a qualitative picture of acyl substituent effects on the intermolecular interactions toward crystal packing of these six structures. Intermolecular interaction energies for dimers observed in these structures calculated by density functional theory (B97D3/def2-TZVP) and PIXEL (MP2/6-31G**) methods are comparable. This study also identifies that multiple hydrogen bonds, including N/C-H···O/N and C-H···π interactions, are collectively responsible for a self-assembled synthon. The nature and strength of these interactions have been studied using atoms in molecule topological analysis. The in vitro antiproliferative activity of compound 1 was assessed against five human tumor cell lines and showed marked antiproliferative activity.

X-ray and theoretical investigation of (Z)-3-(adamantan-1-yl)-1-(phenyl or 3-chlorophenyl)-S-(4-bromobenzyl)isothioureas: an exploration involving weak non-covalent interactions, chemotherapeutic activities and QM/MM binding energy.

A detailed exploration of crystal packing of two adamantane-isothiourea hybrid derivatives along with a known closely related structure has been performed to delineate the effect of halogen substituents and the role of weak intermolecular interactions in their supramolecular architectures. The adamantane-isothiourea hybrid derivatives used in the present study are (Z)-3-(Adamantan-1-yl)-S-(4-bromobenzyl)-1-phenylisothiourea (1), C24H27BrN2S and (Z)-3-(Adamantan-1-yl)-S-(4-bromobenzyl)-1-(3-chlorophenyl)isothiourea (2), C24H26BrClN2S, characterized by X-ray crystallography. The X-ray structures revealed that the molecular conformation of 1 and 2 are different and stabilized by intramolecular C-H···N interactions. In addition, a short intramolecular H···H contact is formed in 2. The Hirshfeld surface analysis was used to delineate the nature of different intermolecular interactions and their contributions toward crystal packing. The quantitative analysis of strengths of molecular dimers existed in 1 and 2 has been performed using the PIXEL method. The electrostatic potential map clearly revealed nature and strength of σ-holes at Br and Cl atoms. The topological analysis was used to characterize the nature and the strength of various intermolecular interactions including the type I Br···Br contact. Interestingly, all the H-H bonding observed in 1 and 2 show closed-shell in nature. Further, an in-vitro antimicrobial activity studies suggest that the title compounds exhibited potent antibacterial activity against all the tested Gram-positive bacterial strains and Gram-negative Escherichia coli. Compound 2 showed marked anti-proliferative activity against MCF-7 and HeLa cell lines.Communicated by Ramaswamy H. Sarma.

Structural and Energetic Properties of Weak Noncovalent Interactions in Two Closely Related 3,6-Disubstituted-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole Derivatives: In Vitro Cyclooxygenase Activity, Crystallography, and Computational Investigations.

Two 3,6-disubstituted-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives, namely, 3-(adamantan-1-yl)-6-(2-chloro-6-fluorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole 1 and 6-(2-chloro-6-fluorophenyl)-3-phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole 2, were prepared, and the detailed analysis of the weak intermolecular interactions responsible for the supramolecular self-assembly was performed using X-ray diffraction and theoretical tools. Analyses of Hirshfeld surface and 2D fingerprint plot demonstrated the effect of adamant-1-yl/phenyl moieties on intermolecular interactions in solid-state structures. The effect of these substituents on H···H/Cl/N contacts was more specific. The CLP-PIXEL and density functional theory methods provide information on the energetics of molecular dimers observed in these compounds. The crystal structure of compound 1 stabilizes with a variety of weak intermolecular interactions, including C-H···N, C-H···π, and C-H···Cl hydrogen bonds, a directional C-S···π chalcogen bond, and unconventional short F···C/N contacts. The crystal structure of compound 2 is stabilized by π-stacking interactions, C-H···N, C-H···π, and C-H···Cl hydrogen bonds, and highly directional attractive σ-hole interactions such as the C-Cl···N halogen bond and the C-S···N chalcogen bond. In addition, S(lp)···C(π) and short N···N contacts play a supportive role in the stabilization of certain molecular dimers. The final supramolecular architectures resulting from the combination of different intermolecular interactions are observed in both the crystal packing. The molecular electrostatic potential map reveals complementary electrostatic potentials of the interacting atoms. The quantum theory of atoms in molecules approach was used to delineate the nature and strength of different intermolecular interactions present in different dimers of compounds 1 and 2. The in vitro experiments suggest that both compounds showed selectivity against COX-2 targets rather than COX-1. Molecular docking analysis showed the binding pose of the compounds at the active sites of COX-1/2 enzymes.

A novel therapeutic combination of dapagliflozin, Lactobacillus and crocin attenuates diabetic cardiomyopathy in rats: Role of oxidative stress, gut microbiota, and PPARγ activation.

AIMS: Diabetic cardiomyopathy is diagnosed by the development of abnormality in the structure and performance of myocardium in diabetic mellitus (DM) patients. Recent studies reported the association between altered gut microbiota and metabolic disorders like diabetes and cardiovascular diseases. Here, we aimed to investigate the gut-heart axis in an experimental animal model where we developed a novel therapeutic combination of dapagliflozin, crocin prebiotic and Lactobacilli probiotic to correct induced diabetic cardiomyopathy. MATERIALS AND METHODS: Diabetes mellitus was induced by Intraperitoneal (i.p) streptozotocin in male rats. The experimental design includes the administration of the tested drugs (Crocin, Dapagliflozin) solely and with Lactobacillus, or in combination therapy with and without Lactobacillus to the diabetic rats for six weeks. Clinical and microscopic evaluation scoring for cardiac tissues were determined. Biochemical markers including blood glucose level, adiponectin, resistin, cardiac injury markers, lipid profile, antioxidant enzymes, pro and anti-inflammatory markers were assessed. In addition, quantitative relative expression of PPARγ and TXINP genes and capsase-3 levels were measured. The change in the microbiota abundance was investigated using real-time PCR. KEY FINDINGS: This study demonstrated the synergistic effect of the triple combination; dapagliflozin, crocin prebiotic, and Lactobacillus fermentum and Lactobacillus delbrueckii probiotic in treating diabetic cardiomyopathy in rats. The triple combination significantly reduced the oxidative, inflammatory, apoptotic activities induced by streptozotocin STZ and helped in restoring the symbiotic gut microbiota. SIGNIFICANCE: It is worthy to perform this study in clinical trials as a primary step to include crocin and Lactobacilli in the therapeutic protocols of diabetic cardiomyopathy.

Ganoderma lucidum ameliorates the diabetic nephropathy via down-regulatory effect on TGFß-1 and TLR-4/NFκB signalling pathways.

OBJECTIVES: Diabetic nephropathy (DN) is one of the most important complications of diabetes mellitus and it is considered as a principal cause for end-stage renal failure. Ganoderma lucidum (GL) has been studied for its reno-protective effect against different kidney injury models. The aim of our study is to investigate the mechanisms by which GL can improve kidney injury and consequent renal inflammation and fibrosis. METHODS: GL either in a low dose (250 mg/kg, i.p.) or high dose (500 mg/kg, i.p.) was administered to DN rat model, and nephropathy indices were investigated. KEY FINDINGS: GL treatment significantly down-regulated kidney injury molecule-1 (KIM-1) gene expression and inhibited TLR-4 (Toll-like receptor-4)/NFκB (nuclear factor kappa B) signalling pathway. As well, GL treatment significantly decreased the pro-inflammatory mediator; IL-1ß (interleukin-1 beta) level and fibrosis-associated growth factors; FGF-23 (fibroblast growth factor-23) and TGFß-1 (transforming growth factor beta-1) levels. In addition, GL remarkably inhibited (Bax) the pro-apoptotic protein and induced (Bcl-2) the anti-apoptotic protein expression in kidneys. Moreover, GL treatment significantly alleviates kidney injury indicated by correcting the deteriorated kidney function and improving oxidative stress status in DN rats. CONCLUSIONS: GL significantly improved renal function indices through dose-dependent kidney function restoration, oxidative stress reduction, down-regulation of gene expression of KIM-1 and TLR4/NFκB signalling pathway blockage with subsequent alleviation of renal inflammation and fibrosis.

Adamantane-linked isothiourea derivatives suppress the growth of experimental hepatocellular carcinoma via inhibition of TLR4-MyD88-NF-κB signaling.

In this study, in vitro cytotoxic effects of seven adamantyl isothiourea derivatives were evaluated against five human tumor cell lines using the MTT assay. Compounds 5 and 6 were found to be the most active derivatives particularly against hepatocellular carcinoma (HCC). To decipher the potential mechanisms involved, in vivo studies were conducted in rats by inducing HCC via chronic thioacetamide (TAA) administration (200 mg/kg, i.p., twice weekly) for 16 weeks. Compounds 5 and 6 were administered to HCC rats, at a dose of 10 mg/kg/day, for further 2 weeks. In vitro and in vivo antitumor activities of compounds 5 and 6 were compared to those of the anticancer drug doxorubicin (DOXO). In the HCC rat model, compounds 5 and 6 significantly reduced serum levels of ALT, AST with ALP and α-fetoprotein. H & E and Masson trichrome staining revealed that both compounds suppressed hepatocyte tumorigenesis and diminished fibrosis, inflammation and other histopathological alterations. Mechanistically, compounds 5 and 6 markedly decreased protein expression levels of α-SMA, sEH, p-NF-κB p65, TLR4, MyD88, TRAF-6, TNF-α, IL-1ß and TGF-ß1, whereas they increased caspase-3 expression in liver tissues of HCC rats. In most analyses, the effects of compound 6 were more comparable to DOXO than compound 5. These findings suggested that the compounds 5 and 6 displayed in vitro and in vivo cytotoxic potential against HCC, probably via inhibition of TLR4-MyD88-NF-κB signaling.