Roselle (Hibiscus sabdariffa L.) extract as an adjunct to valsartan in patients with mild chronic kidney disease: A double-blind randomized controlled clinical trial.

Objective: The objective of this study was to evaluate the effectiveness of Hibiscus sabdariffa L. extract (HS) as an adjunct to valsartan in the treatment of high blood pressure in patients with mild chronic kidney disease (CKD). Materials and Methods: This trial was conducted in Gorgan, Iran. Seventy-two participants with CKD and high blood pressure were randomly assigned to either the HS group, receiving a 350 mg pill every 12 hr for 90 days along with 40 mg of valsartan every 12 hr, or the control group (40 mg valsartan + 12.5 mg hydrochlorothiazide). The primary objective was to assess the improvement of hypertension, while secondary objectives included the evaluation of proteinuria, albuminuria, kidney function, lipid profile, and electrolyte levels. Molecular docking analysis was performed to examine the mechanisms of action of the isolated components of HS. Results: Out of 80 initial participants, 72 were included in the analysis. Both groups showed a significant reduction in blood pressure (p<0.001). The HS group demonstrated a statistically significant decrease in lipid profile (p<0.001). There were no statistically significant differences between the groups regarding the reduction of renal markers. Molecular docking analysis revealed that the compounds present in HS, particularly its anthocyanins and flavonoids, exhibited greater angiotensin-converting enzyme (ACE) inhibitory potential than hydrochlorothiazide in both domains. Moreover, the compounds met the criteria for drug likeness and Lipinski rules. Conclusion: Adjunctive therapy with HS showed promising results in reducing hypertension and improving lipid profile in patients with CKD.

Potential antiplatelet agents with grape seed - backbone polyphenols: computational studies.

The study focused on grape seed-derived polyphenols for their antiplatelet, anti-inflammatory, and fibrinolytic properties through molecular docking and dynamics simulations. Compounds were evaluated for their effects on P2Y12, PTP1B, thromboxane A2, and other targets. Compounds 1 and 6 showed strong inhibitory potential on P2Y12. Compounds 2 and 7, plus epigallocatechin gallate, demonstrated effective inhibition on NF-KB and COX1. The compounds exhibited drug-like properties and potential for new thrombotic disease therapies. The research sheds light on the interactions between polyphenols and target proteins, paving the way for novel antiplatelet strategies.

Potentilla reptans L. preconditioning regulates H19 and MIAT long noncoding RNAs in H9C2 myoblasts Ischemia/Reperfusion model.

The present study aimed to evaluate the effect of the ethyl acetate fraction of P. reptans root (PEF) preconditioning on expressions of lncRNAs H19 and MIAT in H9C2 myoblasts I/R injury.H9C2 cells were treated with different concentrations ranging from (10-400 µg/ml) of PEF for 24 h, followed by simulation of I/R condition. For I/R experiments, H9C2 cells were subjected with the oxygen and glucose deprivation for 2 h.H9C2 cell viability was significantly enhanced by PEF preconditioning under I/R condition in a concentration-dependent manner up to 200 µg/ml as a EC50. The PEF significantly diminished the expression of lncRNA MIAT and rate of apoptosis against the I/R group. In addition, PEF pretreated before stimulation I/R condition increased H19 expression compared to the normal PEF group with no statistically significant differences between groups. Hence, the results suggest that PEF can protect cardiomyocytes during hypoxia-induced myocardial cell injury by targeting specific involved genes.

Prediction of COVID-19 manipulation by selective ACE inhibitory compounds of Potentilla reptant root: In silico study and ADMET profile.

In the novel SARS-CoV-2 (COVID-19) as a global emergency event, the main reason of the cardiac injury from COVID-19 is angiotensin-converting enzyme 2 (ACE2) targeting in SARS-CoV-2 infection. The inhibition of ACE2 induces an increase in the angiotensin II (Ang II) and the angiotensin II receptor type 1 (AT1R) leading to impaired cardiac function or cardiac inflammatory responses. The ethyl acetate fraction of Potentilla reptans L. root can rescue heart dysfunction, oxidative stress, cardiac arrhythmias and apoptosis. Therefore, isolated components of P. reptans evaluated to identify natural anti-SARS-CoV-2 agents via molecular docking. In silico molecular docking study were carried out using the Auto Dock software on the isolated compounds of Potentilla reptans root. The protein targets of selective ACE and others obtained from Protein Data Bank (PDB). The best binding pose between amino acid residues involved in active site of the targets and compounds was discovered via molecular docking. Furthermore, ADMET properties of the compounds were evaluated. The triterpenoids of P. reptans showed more ACE inhibitory potential than catechin in both domains. They were selective on the nACE domain, especially compound 5. Also, the compound 5 & 6 had the highest binding affinity toward active site of nACE, cACE, AT1R, ACE2, and TNF-α receptors. Meanwhile, compound 3 showed more activity to inhibit TXA2. Drug likeness and ADMET analysis showed that the compounds passed the criteria of drug likeness and Lipinski rules. The current study depicted that P. reptans root showed cardioprotective effect in COVID-19 infection and manipulation of angiotensin II-induced side effects.

Investigations of adsorption behavior and anti-inflammatory activity of glycine functionalized Al12N12 and Al12ON11 fullerene-like cages.

The adsorption behavior of the amino acid, glycine (Gly), via the carboxyl, hydroxyl, and amino groups onto the surfaces of Al12N12 and Al16N16 fullerene-like cages were computationally evaluated by the combination of density functional theory (DFT) and molecular docking studies. It was found that Gly can chemically bond with the Al12N12 and Al16N16 fullerene-like cages as its amino group being more favorable to interact with the aluminum atoms of the adsorbents compared to carboxyl and hydroxyl groups. Oxygen and carbon doping were reported to reduce steric hindrance for Glycine interaction at Al site of Al12ON11/Gly and Al12CN11/Gly complexes. Interaction was further enhanced by oxygen doping due to its greater electron withdrawing effect. Herein, the Al12ON11/Gly complex where two carbonyl groups of Gly are bonded to the aluminum atoms of the Al12N12 fullerene-like cage is the most stable interaction configuration showing ∆adsH and ∆adsG values of -81.74 kcal/mol and -66.21 kcal/mol, respectively. Computational studies also revealed the frequency shifts that occurred due to the interaction process. Molecular docking analysis revealed that the Al12N12/Gly (-11.7 kcal/mol) and the Al12ON11/Gly (-9.2 kcal/mol) complexes have a good binding affinity with protein tumor necrosis factor alpha (TNF-α). TNF-α was implicated as a key cytokine in various diseases, and it has been a validated therapeutic target for the treatment of rheumatoid arthritis. These results suggest that the Al12N12/Gly complex in comparison with the Al16N16/Gly, Al12ON11/Gly, and the Al12CN11/Gly complexes could be efficient inhibitors of TNF-α.

Data on molecular docking of tautomers and enantiomers of ATTAF-1 and ATTAF-2 selectivty to the human/fungal lanosterol-14α-demethylase.

The data have been obtained for tautomers and enantiomers of ATTAF-1 and ATTAF-2 that were developed based on antifungal standard drugs with triazole scaffold. These compounds were docked into the human and fungal lanosterol-14α-demethylase. In order to validate the data, 8 standard triazole antifungal drugs (Fluconazole, Itraconazole, Posaconazole, Ravuconazole, Albaconazole, Voriconazole, Isavuconazole and Efinaconazole) were also docked into the human and fungal lanosterol-14α-demethylase. The binding conformations of these molecules and their interactions with lanosterol-14α-demethylase may inform the development of further small molecule lanosterol-14α-demethylase inhibitors with significant selectivity toward this enzyme. The analysis has done on the basis of type of interactions (bond type and distance). The length of the Fe-N coordination bond for (R)-N2-ATTAF-1 and (S)-N1-ATTAF-2 complexes is obtained 6.36 and 4.19 Å, respectively and about 2 Šin the other tautomer and enantiomer complexes, reflecting the lower basicity of the N-4 atom in the 1,2,4-triazole ring of (R)-N2-ATTAF-1 and (S)-N1-ATTAF-2 in comparison with the N-4 atom in the 1,2,4-triazole ring in other tautomers and enantiomers and supporting higher selectivity of (R)-N2-ATTAF-1 and (S)-N1-ATTAF-2 towards the target CYP51 enzymes vs. human. Interestingly, we have investigated unfavorable interactions (donor-donor) with TRP239 and MET378 for (R)-N2-ATTAF-1 and (S)-N1-ATTAF-2, respectively. These unfavorable interactions also have been seen in case of posaconazole and isavuconazole. The data presented in this article are related to the research paper entitled "In silico prediction of ATTAF-1 and ATTAF-2 selectivity towards human/fungal lanosterol 14α-demethylase using molecular dynamic simulation and docking approaches".

Indole-derived chalcones as anti-dermatophyte agents: In vitro evaluation and in silico study.

A series of indole-derived methoxylated chalcones were described as anti-dermatophyte agents. The in vitro antifungal susceptibility testing against different dermatophytes revealed that most of compounds had potent activity against the dermatophyte strains. In particular, the 4-ethoxy derivative 4d with MIC values of 0.25-2 µg/ml was the most potent compound against Trichophyton interdigitale, Trichophyton veruccosum and Microsporum fulvum. Moreover, the 4-butoxy analog 4i displaying MIC values in the range of 1-16 µg/ml had the highest inhibitory activity against Trichophyton mentagrophytes, Microsporum canis, and Arthroderma benhamiae. To predict whether the synthesized compounds interact with tubulin binding site of dermatophytes, the 3D-structure of target protein was modeled by homology modeling and then used for molecular docking and molecular dynamics (MD) simulation studies. Docking simulation revealed that the promising compound 4d can properly bind with tubulin. The molecular dynamics analysis showed that interactions of compound 4d with the active site of target protein have binding stability throughout MD simulation. The results of this study could utilize in the design of more effective antifungal drugs with tubulin inhibition mechanism against keratinophilic fungi.

Design, synthesis and biological evaluation of flexible and rigid analogs of 4H-1,2,4-triazoles bearing 3,4,5-trimethoxyphenyl moiety as new antiproliferative agents.

Several flexible and rigid analogs of 4H-1,2,4-triazoles (compounds 8a-g and 9a-g) bearing trimethoxyphenyl pharmacophoric unit, were designed and synthesized as potential anticancer agents. The in vitro cytotoxic assay indicated that both flexible and rigid analogs (8 and 9, respectively) can potentially inhibit the growth of cancerous cells (A549, MCF7, and SKOV3), with IC50 values less than 5.0 µM. Furthermore, compounds 10a-l as regional isomers of compounds 9 exhibited remarkable cytotoxic activity with IC50 values ranging from 0.30 to 5.0 µM. The rigid analogs 9a, 10h and 10k were significantly more potent than etoposide against MCF7, SKOV3 and A549 cells, respectively. These compounds showed high selectivity towards cancer cells over normal cells, as they had no significant cytotoxicity against L929 cells. In addition, the representative compounds 9a and 10h could inhibit the tubulin polymerization at micro-molar levels. By determining changes in the colchicine-tubulin fluorescence, it was suggested that compound 10h could bind to the tubulin at the colchicine pocket. The molecular docking study further confirmed the inhibitory activity of promising compounds 9a, 10h and 10k on tubulin polymerization through binding to the colchicine-binding site.

Repurposing azole antifungals into antileishmanials: Novel 3-triazolylflavanones with promising in vitro antileishmanial activity against Leishmania major.

Previously, we have described a series of azole antifungals namely 3-(1,2,4-triazol-1-yl)flavanones (TFs) containing an N-(phenethyl)azole framework required for sterol 14α-demethylase (CYP51) inhibitory activity. Similar mechanism of action of azoles in fungi and protozoan parasites prompted us to investigate the potential effects of TFs against promastigote and amastigote forms of Leishmania major (L. major), as well as their toxicity against macrophages, apoptosis induction and in silico interactions with the target enzyme. All compounds showed more potent anti-parasitic activity against L. major in comparison with reference azole drug fluconazole and standard antileishmanial agent glucantime. Among the tested compounds, the 4-chloro derivative (TF-2) was found to be the most potent one, being about 13 times more potent than fluconazole against promastigotes. TF-2 decreased both mean infection rate of macrophages (MIR) and mean number of amastigotes per macrophages (MNAPM), significantly more than fluconazole (P < .001). Furthermore, the cytotoxicity assay against J774.A.1 macrophages revealed that this compound displays high selectivity against amastigotes over macrophages (SI = 30.21). The in silico study showed that TF-2 can properly accommodated in the active site of parasitic CYP51 and coordinated to the heme. The SAR analysis showed that the introduction of 4-chloro on 2-phenyl moiety results in the best profile of activity and selectivity. Accordingly, the compound TF-2 prototype can be considered as promising candidate for development of new antileishmanial agents.

Acetophenone benzoylhydrazones as antioxidant agents: Synthesis, in vitro evaluation and structure-activity relationship studies.

Acetophenone and its analogues are naturally-occurring compounds found in many foods and plants. In this study, a series of acetophenone benzoylhydrazones 5a-o were designed and synthesized as new potential antioxidant agents. Designed molecules contain hydrazone and phenolic hydroxyl moieties which possibly contribute to antioxidant activity. The antioxidant properties of compounds 5a-o in terms of reducing ability and radical-scavenging activity were assessed by using FRAP and DPPH tests, respectively. While the unsubstituted compound 5a had the superior capacity in the FRAP assay, the 2,4-dihydroxyacetophenone analogue 5g was the most potent radical scavenger in the DPPH method. The antioxidant potential of representative compounds 5a and 5g was further confirmed by TEAC and ORAC assays. Cell viability assays revealed that while the promising compounds 5a and 5g had no significant toxicity against HepG2 and NIH3T3 cells, they potently protected HepG2 cells against H2O2-induced oxidative damage at low concentrations. Furthermore, spectroscopic studies with different biometals demonstrated that 5g was able to interact with Cu2+ to form a 1:1 complex.

Promising antileishmanial activity of novel imidazole antifungal drug luliconazole against Leishmania major: In vitro and in silico studies.

OBJECTIVES: Pentavalent antimonials have been used for the treatment of leishmaniasis for over 70 years, however they are limited by their toxicity. Unfortunately, the efficacy of first-line drugs for the treatment of leishmaniasis has decreased and resistance is noticeable. Luliconazole is a new azole with unique effects on fungi that has not yet been tested on Leishmania parasites. METHODS: In this study, the cytotoxicity and antileishmanial activity of luliconazole were evaluated in vitro against promastigotes and intracellular amastigotes of Leishmania major. The docking simulation with the target enzyme, sterol 14α-demethylase (CYP51) was performed using AutoDock 4.2 program. RESULTS: The IC50 (concentration of test compound required for 50% inhibition) against promastigotes revealed that luliconazole (IC50=0.19µM) has greater potency than ketoconazole (KET), meglumine antimoniate (MA) and amphotericin B (AmB) (IC50 values of 135, 538 and 2.52µM, respectively). Against the amastigote stage, luliconazole at a concentration of 0.07µM decreased the mean infection rate and the mean number of amastigotes per macrophage more effectively than MA (P<0.004) and KET (P<0.043), but there was no difference compared with AmB (P>0.05). A docking study of luliconazole with the cytochrome P450 enzyme sterol 14α-demethylase (CYP51) revealed that this azole drug can properly interact with the target enzyme in Leishmania mainly via coordination with heme and multiple hydrophobic interactions. CONCLUSION: These results show the potent activity of luliconazole at extremely low concentrations against L. major. It may therefore be considered as a new candidate for treatment of leishmaniasis in the near future.

Discovery of benzylthio analogs of fluconazole as potent antifungal agents.

AIM: A new series of triazole alcohol antifungals 8a-j were designed by introducing benzylthio functionality on one triazole ring of fluconazole. RESULTS: The antifungal activity evaluation of target compounds against 16 Candida isolates indicated that all compounds with MIC values of 0.063-1 µg/ml had better profile of activity in respect to fluconazole (MICs = 0.5-4 µg/ml) against fluconazole-susceptible isolates. In particular, the representative compounds 8b and 8e were also active against fluconazole-resistant isolates of Candida albicans and Candida parapsilosis (MICs = 0.063-16 µg/ml). Cytotoxicity assay against Hep-G2 and NIH-3T3 cell lines revealed that these compounds can display potent antifungal activity at noncytotoxic concentrations. CONCLUSION: The prototype compound 8b could be considered as a new lead for design and development of potent antifungal agents. [Formula: see text].

New indole-based chalconoids as tubulin-targeting antiproliferative agents.

Tubulin-targeting compounds have a broad anticancer spectrum and are an important class of chemotherapeutic agents. Due to the importance of 3-bromo-3,5-dimethoxyphenyl scaffold in the anticancer activity of microtubule inhibitors such as crolibulin (EPC2407), we introduced this functionality into the indole-derived chalcones. Thus, we describe here the synthesis and biological evaluation of new indole-based chalconoids as tubulin-targeting antiproliferative agents. The best result was obtained by compound 9b against A549 cell with IC50 of 4.3µg/mL, being more potent than the reference drug etoposide. Further biological evaluations revealed that compound 9b can inhibit tubulin polymerization and decrease the mitochondrial thiol content, resulting the induction of apoptosis in cancer cells. Docking studies with tubulin indicated that compound 9b could bind to the colchicine binding site.

Recent advances of cytotoxic chalconoids targeting tubulin polymerization: Synthesis and biological activity.

Since microtubules have an important role in mitosis and other vital cellular functions, tubulin-targeting chemotherapy has been received growing attention in anticancer drug design and development. It was found that a number of naturally occurring compounds including distinct chalcones exert their effect by inhibition of tubulin polymerization. After the identification of tubulin polymerization as potential target for chalcone-type compounds, extensive researches have been made to design and synthesis of new anti-tubulin chalconoids. Although diverse chalcones have found to be potent anticancer agents but in the present review, we focused on the recently reported tubulin polymerization inhibitors from chalcone origin and related synthetic compounds, and their detailed synthetic methods and biological activities.

Polymorphism of Pro12Ala in the peroxisome proliferator-activated receptor gamma2 gene in Iranian diabetic and obese subjects.

BACKGROUND: Peroxisome proliferator-activated receptor gamma2 (PPARgamma2) is a nuclear receptor that regulates adipocyte differentiation, lipid metabolism, and insulin sensitivity. The aim of this study was to investigate the association between the Pro12Ala single nucleotide polymorphism (SNP) at the PPARgamma2 gene and type II diabetes (T2DM) and obesity in an Iranian population. METHODS: The genomic DNA of the 312 subjects included four groups: (1) nonobese with type II diabetes, (2) obese without type II diabetes, (3) obese with type II diabetes, and (4) nondiabetic nonobese controls. The Pro12Ala polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. RESULTS: Frequencies of the Ala allele in obese subjects were significantly different from those control subjects (odds ratio [OR], 2.358; 95% confidence interval [CI], 1.101-5.05) (P = 0.025). In contrast, no significant association was detected between the Pro12Ala polymorphism and type II diabetes (OR, 0.652; 95% CI, 0.261-1.628). In all subjects, the Ala carriers had a higher body mass index (BMI) compared with the common allele. CONCLUSIONS: Our results showed that the Pro12Ala polymorphism in the PPARgamma2 gene is associated with obesity in Iranian subjects and the presence of the Ala allele could predict higher BMI.