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Abstract Background Obstructive sleep apnea (OSA) is one of the foremost potential severe disorders, with frequent episodes of complete or partial obstructions of the upper airway during sleep. Therefore, several attempts to find an effective pharmacotherapy by repurposing several drugs such as serotonin reuptake inhibitors (SRIs) and norepinephrine and dopamine reuptake inhibitors (NDRIs) were recently considered as alternative therapeutic strategy. So, in this review, we will present non-conventional pharmacological approaches for managing OSA via either repurposing selected natural products or traditional medicine. Evidence acquisition Scientific databases and literature reviewed in the last twenty years were screened using different keywords related to OSA; exclusion criteria were applied based on the accessibility and the ability of the sources to follow evidence-based approaches. The eligible resources were classified into two main categories: clinical-based studies and preclinical studies. The findings of these studies were analyzed and discussed in light of current evidence derived from recent studies. Findings Several natural components and traditional formulas were found to regulate several molecular targets involved in OSA pathogenesis, supported by several in-vitro and in-vivo studies. Also, natural products subjected to clinical trials give promising results. Still, there are some limitations, such as involving a small number of patients depending on subjective yet acceptable scores rather than objective scores, a lack of positive control groups, or a small number of patients. Conclusion Therapeutic protocols should consider non-conventional polypharmacological strategies targeting all OSA aspects. Hence, there is an opportunity to reposition some well-defined natural products, such as cinnamic acid derivatives, isoflavones, and lignans, as several evidences from in-vitro, in-vivo, and clinical trials support their potential efficacy in the management of OSA.

A novel analogue of hybrid spirooxindoles was synthesized employing a systematic multistep synthetic approach. The synthetic protocol was designed to obtain a series of spirooxindole derivatives incorporating triazolyl-s-triazine framework via [3 + 2] cycloaddition (32CA) reaction of azomethine ylide (AY) with the corresponding chalcones (6a-d). Unexpectedly, the reaction underwent an alternate route, leading to the cleavage of the s-triazine moiety and yielding a series of spirooxindole derivatives incorporating a triazole motif. A comprehensive investigation of the 32CA reaction mechanism was conducted using Molecular Electron Density Theory (MEDT). The viability of all compounds was evaluated through an MTT assay, and the IC50 values were determined using Prism Software. The antiproliferative efficacy of the synthesized chalcones and the corresponding spirooxindole derivatives was assessed against two cancer cell lines: MDA-MB-231 (triple-negative breast cancer) and HepG2 (human hepatoma). These findings were compared with Sorafenib, which was used as a positive control. The results revealed that chalcones (6c and 6d) were the most active among the tested chalcones, with IC50 values of 7.2 ± 0.56 and 7.5 ± 0.281 µM for (6c) and of 11.1 ± 0.37 and 11.0 ± 0.282 µM for (6d), against MDA-MB-231 and HepG2, respectively. Spirooxindoles (9b, 9c, 9h, and 9i) exhibited the highest activity with IC50 values ranging from 16.8 ± 0.37 µM to 31.3 ± 0.86 µM against MDA-MB-231 and 13.5 ± 0.92 µM to 24.2 ± 0.21 µM against HepG2. In particular, spirooxindole derivatives incorporating 2,4-dichlorophenyl moiety were the most active, with an IC50 of 16.8 ± 0.37 µM for (9h) against MDA-MB-23 and 13.5 ± 0.92 µM for (9i) against HepG2. Interestingly, the IC50 of compound (6c) (7.2 µM) exhibited better activity than that of Sorafenib (positive control) (9.98 µM) against MDA-MB-231. Molecular docking, ADMET, and molecular dynamic simulations were conducted for the promising candidates (6b, 6c, and 9h) to explore their binding affinity in the EGFR active site.

SARS-CoV-2 pandemic in the end of 2019 led to profound consequences on global health and economy. Till producing successful vaccination strategies, the healthcare sectors suffered from the lack of effective therapeutic agents that could control the spread of infection. Thus, academia and the pharmaceutical sector prioritise SARS-CoV-2 antiviral drug discovery. Here, we exploited previous reports highlighting the anti-SARS-CoV-2 activities of isatin-based molecules to develop novel triazolo-isatins for inhibiting main protease (Mpro) of the virus, a crucial enzyme for its replication in the host cells. Particularly, sulphonamide 6b showed promising inhibitory activity with an IC50= 0.249 µM. Additionally, 6b inhibited viral cell proliferation with an IC50 of 4.33 µg/ml, and was non-toxic to VERO-E6 cells (CC50 = 564.74 µg/ml) displaying a selectivity index of 130.4. In silico analysis of 6b disclosed its ability to interact with key residues in the enzyme active site, supporting the obtained in vitro findings.

The biotransformation of vulgarin (1), an eudesmanolides-type sesquiterpene lactone obtained from Artemisia judaica, by the microorganism, Aspergillus niger, was carried out to give three more polar metabolites; 1-epi-tetrahydrovulgarin (1α,4α-dihydroxy-5αH,6,11βH-eudesman-6,12-olide (2), 20% yield, 1α,4α-dihydroxyeudesm-2-en-5αH,6,11βH-6,12-olide (3a), 10% yield, and C-1 epimeric mixture (3a, b), 4% yield, in a ratio of 4:1, 3a/3b. The structures of vulgarin and its metabolites were elucidated by 1 and 2D NMR spectroscopy in conjunction with HRESIMS. Metabolites (3a) and (3b) are epimers, and they are reported here for the first time as new metabolites obtained by biotransformation by selective reduction at C-1. Vulgarin and its metabolites were evaluated as anti-inflammatory agents using the human cyclooxygenase (COX) inhibitory assay. The obtained data showed that (1) exhibited a good preferential inhibitory activity towards COX-2 (IC50 = 07.21 ± 0.10) and had a moderate effect on COX-1 (IC50 = 11.32 ± 0.24). Meanwhile, its metabolite (3a) retained a selective inhibitory activity against COX-1 (IC50 = 15.70 ± 0.51). In conclusion, the results of this study revealed the necessity of the presence α, β unsaturated carbonyl group in (1) for better COX-2 inhibitory activity. On the other hand, the selectivity of (1) as COX-1 inhibitor may be enhanced via the reduction of C-1 carbonyl group.

Ovarian cancer (OC) is the 7th most common cancer in women world-wide and the 3rd most common female cancer. For the treatment of OC, there is no successful therapeutic. The medications that are currently available have significant side effects and a low therapeutic index. This work aimed to evaluate the anticancer activity of organoselenium pseudopeptide compound against OC cell lines. After treatment with 50 ​μM of compound 4 (CPD 4), the viability was determined. The anticancer activity was further investigated by different methods including cell cycle and apoptosis analysis, colony formation assay, zymography, comet assay and Western blot. In comparison to a positive control, compound 4 showed cytotoxicity toward A2780CP cells rather than A2780 and SKOV-3 ​cells. Compound 4 was more selective to OC cells rather than HSF cells. Moreover, Compound 4 was able to inhibit cell migration and proliferation. The anticancer effect of compound 4 was found to be partially via cell cycle arrest, overexpression of p27 ​cell cycle inhibitor and induction of apoptosis through DNA fragmentation and activated production of ROS. Compound 4 had a differential effect on the modulation of PI3K/AKT/mTOR signaling pathway in the OC treated cell lines, also inhibited lipogenesis process via downregulation of FASN expression. Conclusion: This work highlights the unique role of Compound 4 against OC via modulation of oxidative stress, inhibition of survival PI3K/AKT/mTOR pathway. Compound 4 was found to be a promising alternative therapy for the treatment of OC in this investigation.

The poor solubility and stability of 6-gingerol (6-G) could hamper its clinical applications. The aim of the current study was to develop a novel ultra-deformable cyclodextrin-functionalized transethoniosomes (CD-TENs) as a promising delivery system for 6-G. Transethoniosomes (TENs) are flexible niosomes (NVs) due to their content of ethanol and edge activators (EAs). CD-functionalized nanoparticles could improve drug solubility and stability compared to the corresponding nanovesicles. 6-G-loaded ethoniosomes (ENs) were formulated by the ethanol injection technique in the presence and absence of EA and CD to explore the impact of the studied independent variables on entrapment efficiency (EE%) and % 6-G released after 24 h (Q24h). According to the desirability criteria, F8 (CD-functionalized transethoniosomal formula) was selected as the optimized formulation. F8 demonstrated higher EE%, permeation, deformability and stability than the corresponding TENs, ENs and NVs. Additionally, F8 showed higher cytotoxic and anti-inflammatory activity than pure 6-G. The synergism between complexation with CD and novel ultra-deformable nanovesicles (TENs) in the form of CD-TENs can be a promising drug delivery carrier for 6-G.

Diagnosis of deadly diseases, such as liver fibrosis, is very important. Clinical decision support systems (CDSSs) based on patient's historical medical data and accurate AI techniques can aid physicians in their decision-making process. The task of arriving at an accurate and timely diagnosis decision is always complex because of the dynamic, vagueness, and uncertainty associated with this disease. Fuzzy logic can perfectly handle these issues. In recent years, two of the most interesting techniques are a fuzzy analytical hierarchy process (FAHP) and an adaptive neuro-fuzzy inference system (ANFIS). The FAHP is popular for dealing with uncertainty in multi-criteria decision-making, and the ANFIS is popular in learning fuzzy inference system from data based on artificial neural networks. To the best of our knowledge, these two methods have not been used to model CDSSs in fibrosis stage detection domain. In this paper, we develop a CDSS based on a case comparison of the effectiveness of the FAHP and the ANFIS in the medical diagnosis of the fibrosis disease. We carefully design and implement two frameworks based on these two techniques. Diagnostic real data of 119 cases infected by chronic viral hepatitis C from the Liver Institute at Mansoura University in Egypt are used to train and test both the FAHP and ANFIS. Criteria and subcriteria weights are based on opinions of two domain experts. The ANFIS model is designed using trial and error based on the analysis of various experiments. Results are later compared with the diagnostic conclusions of medical expert and other three medical and fuzzy techniques. The comparison results show that these two techniques can successfully be employed in designing a diagnostic CDSS system for fibrosis diagnosis. The two techniques achieve a classification accuracy of 93.3%. The results confirm the efficiency and effectiveness of both methods. Therefore, both the FAHP and ANFIS are viable approaches in modeling CDSS for diagnosis of a liver fibrosis stage.

We herein report a new small library of Schiff-base compounds that encompasses s-triazine and (2 or 4)-hydroxylbenzylidene derivatives. These compounds were synthesized through a hydrazone linkage connecting both the s-triazine and hydroxybenzylidene derivatives. The synthetic strategy adopted allowed the synthesis of the target compounds with excellent yields and purities as observed from their NMR (1H and 13C) and elemental analysis. Furthermore, 4f, 5b, and 5f were further confirmed by X-ray single crystal diffraction technique. The preliminary antiproliferative activities for the synthesized compounds were tested against two different cancer cell lines including breast cancer (MCF-7) and colon cancer (HCT-116). From the eighteen compounds, which have been examined, only two derivatives having piperidine moiety showed more selectivity against the two cell lines MCF-7 and HCT-116, while the others showed very weak activity. The position of the hydroxyl group in the benzylidine ring and the substituent on the s-triazine moiety has great effect on the activity of the prepared compounds. The IC50 values for the two derivatives 4a and 5a evaluated against breast cancer cells, very close to those for the chemotherapeutic drug cisplatin, are 27 µM (13.3 µg/mL), 17 µM (8.4 µg/mL), and 20 µM (6 µg/mL) for 4a, 5a, and cisplatin, respectively. These results propose the preliminary antiproliferative activity of these two derivatives may deserve further consideration for development of new derivatives as potent anticancer agents.

A new lupane caffeoyl ester, lup-20(29)-ene 3β-caffeate-30-al (7), and a new oleanane-type triterpene, 3β-hydroxyolean-13(18)-en-12-one (17), were isolated from the aerial parts of Dobera glabra (Forssk), along with ten known triterpenes, including seven lupane-type lupeol (1), 30-nor-lup-3β-ol-20-one (2), ∆1-lupenone (3), lup-20(29)-en-3β,30-diol (4), lupeol caffeate (5), 30-hydroxy lup-20(29)-ene 3β-caffeate (6), and betunaldehyde (8); three oleanane-type compounds were also identified, comprising δ-amyrone (15), δ-amyrin (16), and 11-oxo-β-amyrin (18); together with six sterols, comprising β-sitosterol (9), stigmasterol (10), 7α-hydroxy-β-sitosterol (11), 7α-hydroxy-stigmasterol (12), 7-keto-β-sitosterol (13), and 7-keto-stigmasterol (14). Their structures were elucidated using a variety of spectroscopic techniques, including 1D (1H, 13C, and DEPT-135 13C) and 2D (1H–1H COSY, 1H–13C HSQC, and 1H–13C HMBC) nuclear magnetic resonance (NMR) and accurate mass spectroscopy. Subsequently, the different plant extracts and some of the isolated compounds (1–9, 11 and 13) were investigated for their possible cytotoxic activity in comparison to cisplatin against a wide array of aggressive cancer cell lines, such as colorectal cancer (HCT-116), hepatocellular carcinoma (HepG-2), and prostate cancer (PC-3) cell lines. Compound 11 displayed broad cytotoxicity against all of the tested cell lines (IC50 ≅ 8 µg/mL in all cases), and a high safety margin against normal Vero cells (IC50 = 70 µg/mL), suggesting that 11 may be a highly selective and effective anticancer agent candidate. Notably, the evidence indicated that the mode of action of compound 11 could possibly consist of the inhibition of phosphodiesterase I (80.2% enzyme inhibition observed at 2 µM compound concentration).

Curcumin is a natural compound that has many medical applications. However, its low solubility and poor stability could impede its clinical applications. The present study aimed to formulate dry proniosomes to overcome these pitfalls and improve the therapeutic efficacy of Curcumin. Curcumin-loaded proniosomes were fabricated by the slurry method according to 32 factorial design using Design-Expert software to demonstrate the impact of different independent variables on entrapment efficiency (EE%) and % drug released after 12 h (Q12h). The optimized formula (F5) was selected according to the desirability criteria. F5 exhibited good flowability and appeared, after reconstitution, as spherical nanovesicles with EE% of 89.94 ± 2.31% and Q12h of 70.89 ± 1.62%. F5 demonstrated higher stability and a significant enhancement of Q12h than the corresponding niosomes. The docking study investigated the ability of Curcumin to bind effectively with the active site of DNA polymerase of Herpes simplex virus (HSV). The antiviral activity and the safety of F5 were significantly higher than Curcumin. F5 improved the safety of Acyclovir (ACV) and reduced its effective dose that produced a 100% reduction of viral plaques. Proniosomes could be promising stable carriers of Curcumin to be used as a safe and efficient antiviral agent.

Hyaluronidase enzyme (HAase) has a role in the dissolution or disintegration of hyaluronic acid (HA) and in maintaining the heathy state of skin. Bioassay-guided fractionation of Ravenala madagascariensis (Sonn.) organ extracts (leaf, flower, stem, and root) testing for hyaluronidase inhibition was performed followed by metabolic profiling using LC–HRMS. Additionally, a hyaluronidase docking study was achieved using Molecular Operating Environment (MOE). Results showed that the crude hydroalcoholic (70% EtOH) extract of the leaves as well as its n-butanol (n-BuOH) partition showed higher HAase activity with 64.3% inhibition. Metabolic analysis of R. madagascariensis resulted in the identification of 19 phenolic compounds ranging from different chemical classes (flavone glycosides, flavonol glycosides, and flavanol aglycones). Bioassay-guided purification of the leaf n-BuOH partition led to the isolation of seven compounds that were identified as narcissin, rutin, epiafzelechin, epicatechin, isorhamnetin 7-O-glucoside, kaempferol, and isorhamnetin-7-O-rutinoside. The docking study showed that narcissin, rutin, and quercetin 3-O-glucoside all interact with HAase through hydrogen bonding with the Asp111, Gln271, and/or Glu113 residues. Our results highlight Ravenala madagascariensis and its flavonoids as promising hyaluronidase inhibitors in natural cosmetology preparations for skin care.

A one-pot, single-step, and an atom-economical process towards the synthesis of highly functionalized spirooxindoles analogues was efficiently conducted to produce a satisfactory chemical yields (70−93%) with excellent relative diastereo-, and regio-selectivity. An in vitro antiproliferative assay was carried out on different cancer cell lines to evaluate the biological activity of the synthesized tetrahydro-1’H-spiro[indoline-3,5’-pyrrolo[1,2-c]thiazol]-2-one 5a−n. The prepared hybrids were then tested in vitro for their antiproliferative effects against three cancer cell lines, namely, HepG2 (liver cancer), MCF-7 (breast cancer), and HCT-116 (colon cancer). The spirooxindole analogue 5g exhibited a broad activity against HepG2, MCF-7, and HCT-116 cell lines of liver, breast, and colorectal cancers when compared to cisplatin. Modeling studies including shape similarity, lipophilicity scores, and physicochemical parameters were calculated. The results of this study indicated that spirooxindole analogue 5g retained a good physiochemical parameters with acceptable lipophilicity scores.

New series of 1,2,4-triazolopyrimidine and 1,2,4-triazoloquinazoline derivatives were designed, synthesized, and evaluated for their antitumor activity. Compounds 6, 11, 26, 29, 41, 44, 48, 49 and 58 were tested as antitumor agents by the use of DNA-binding assay on TLC-plates, colorimetric assay for the degree of DNA-binding (Methyl green-DNA displacement assay), evaluation of antineoplastic activity against Ehrlich Ascites Carcinoma in mice, and finally modulation of apoptosis. 5-Flurouracil, vitamin C and ethidium bromide were used as positive controls in these techniques. Compound 26 proved to be the most active member of these series as antitumor agent with IC50 value of 47 ± 1. Several characteristic features were observed to be essential for activity such as the morpholine group and the phenylazo group, in addition the electron-withdrawing groups favor the activity than the electron-donating ones.

The crystal structures of five new chalcones derived from N-ethyl-3-acetylindole with different substituents were investigated: (E)-3-(4-bromophenyl)-1-(1-ethyl-1H-indol-3-yl)prop-2-en-1-one (3a); (E)-3-(3-bromophenyl)-1-(1-ethyl-1H-indol-3-yl)prop-2-en-1-one (3b); (E)-1-(1-ethyl-1H-indol-3-yl)-3-(4-methoxyphenyl)prop-2-en-1-one (3c); (E)-1-(1-ethyl-1H-indol-3-yl)-3-mesitylprop-2-en-1-one (3d); and (E)-1-(1-ethyl-1H-indol-3-yl)-3-(furan-2-yl)prop-2-en-1-one (3e). The molecular packing of the studied compounds is controlled mainly by C−H⋅⋅⋅O hydrogen bonds, C−H⋅⋅⋅π interactions, and π···π stacking interactions, which were quantitatively analyzed using Hirshfeld topology analysis. Using density functional theory (DFT) calculations, the order of polarity (3b ˂ 3d ˂ 3e ˂ 3a ˂ 3c) was determined. Several chemical reactivity indices such as the ionization potential (I), electron affinity (A), chemical potential (μ), hardness (η), electrophilicity (ω) and nucleophilicity (N) indices were calculated, and these properties are discussed and compared. In addition, the antiproliferative activity of the five new chalcones was studied.

An efficient and practical method for the synthesis of 2,6-diaryl-4-oxo-N,N′-di(pyridin-2-yl)cyclohexane-1,1-dicarboxamide is described in this present study, which occurs through a double Michael addition reaction between diamide and various dibenzalacetones. The reaction was carried out in dichloromethane (DCM) in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The anticancer activities of the synthesized compounds were evaluated in several cancer cell lines, including MCF-7, MDA-MB-231, SAS, PC-3, HCT-116, HuH-7 and HepG2 cells. From these experiments, we determined that MDA-MB-231 was the most sensitive cancer cell line to the compounds 3c, 3e, 3d, 3j and 3l, which exhibited variable anticancer activities (3l [IC50 = 5 ± 0.25 µM] > 3e [IC50 = 5 ± 0.5 µM] > 3c [IC50 = 7 ± 1.12 µM] > 3d [IC50 = 18 ± 0.87 µM] > 3j [IC50 = 45 ± 3 µM]). Of these, 3l (substituted p-trifluoromethylphenyl and chloropyridine) showed good potency (IC50 = 6 ± 0.78 µM) against HCT-116 colorectal cancer cells and exhibited high toxicity against HuH-7 liver cancer cells (IC50 = 4.5 ± 0.3 µM). These values were three times higher than the values reported for cisplatin (IC50 of 8 ± 0.76 and 14.7 ± 0.5 µM against HCT-116 and HuH-7 cells, respectively). The highest α-glucosidase inhibitory activity was detected for the 3d, 3i and 3j compounds. The details of the binding mode of the active compounds were clarified by molecular docking studies.