key: cord-0861585-bph7xrbt authors: Alkahtani, Saad A.; Mahmoud, Ashraf M.; Mahnashi, Mater H.; AlQarni, Ali O.; Alqahtani, Yahya S.A.; El-Wekil, Mohamed M. title: Facile one pot sonochemical synthesis of layered nanostructure of ZnS NPs/rGO nanosheets for simultaneous analysis of daclatasvir and hydroxychloroquine date: 2021-01-21 journal: Microchem J DOI: 10.1016/j.microc.2021.105972 sha: 7e711cdc270ecd5a28fe05d44c12cfdd6b0b4201 doc_id: 861585 cord_uid: bph7xrbt In this study, zinc sulfide nanoparticles were loaded on reduced graphene oxide (ZnS NPs/rGO) using simple sonochemical method. The nanocomposite was characterized using different morphological and electrochemical techniques such as TEM, SEM, PXRD, EDX, Raman spectroscopy, FTIR, N(2)-adsorption-desorption, CV, and EIS. The ZnS NPs/rGO modified glassy carbon electrode (GCE) was used to simultaneously estimate hydroxychloroquine (HCQ) and daclatasvir (DAC) in a binary mixture for the first time. The modified nanocomposite exhibited good catalytic activity towards HCQ and DAC detection. In addition, it showed higher sensitivity, good selectivity and stability; and high reproducibility towards HCQ and DAC analysis. The activity of the modified electrode was noticeably improved due to synergism between ZnS NPs and rGO. Under optimum conditions of DPV measurements, the anodic peak currents (Ipa) were obviously increased with the increase of HCQ and DAC amounts with linear ranges of 5.0-65.0 and 7.0-65.0 nM with LODs of 0.456 and 0.498 nM for HCQ and DAC, respectively. The ZnS NPs/ rGO modified GCE was used to quantify HCQ and DAC in biological fluids with recoveries of 98.7-102.7 % and 96.9-104.5 % and RSDs of 1.89-3.57 % and 1.91-3.70 %, respectively. Coronavirus disease has focused great attention on the urgent need to develop effective therapies against the causative agent, SARS-CoV-2 [1] [2] [3] . Daclatasvir (DAC), anti-viral agent, can bind to the replication complex components of 2019-nCoV with an inhibitory potency with Kd of 23.31 nm [4] . Hydroxychloroquine (HCQ) was used as a bioactive agent, and was reported to possess antiviral activities against RNA viruses as hepatitis C virus [5] , hepatitis A virus [6] , influenza A H5N1 virus [7] , Ebola virus [8] , as well as DNA viruses such as herpes simplex virus [9] and hepatitis B virus [10] . Recent publications support the hypothesis that HCQ can improve the clinical outcome of patients infected by SARS-CoV-2. Anti-SARS-CoV-1 actions of HCQ in vitro were attributed to a deficit in the glycosylation of a virus cell surface receptor, the angiotensin-converting enzyme 2 (ACE2) on Vero E6 cells [11] [12] . Sonochemical technique is an efficient, simple and economic method for synthesis of nanomaterials. It provides shorter reaction times and more energy efficiency with an environmental friendly technique [13, 14] . Due to their low cost, plenty of morphologies, good electro-catalytic activity, high surface area and promoting electron transfer, inorganic nanomaterials have attracted more interest as sensors and biosensors [15] [16] [17] [18] [19] [20] [21] . Among them, zinc sulfide (ZnS) has been greatly used due to several advantages such as low cost, non-toxic, easily fabricated, high capacitance and good stability [22] . Reduced graphene oxide (rGO) is considered an ideal electrochemical nanomaterial for different applications due to its unique chemical, electrical and optical properties [23] [24] [25] [26] . The advantages of rGO are ease of preparation (from graphene oxide), stable dispersion in water and high number of catalytic sites on its surface [27] [28] [29] . In addition, rGO interacts with ZnS NPs by the means of electrostatic interactions [30] . Therefore, our approach based on the synthesis of ZnS NPs@ rGO by facile sonochemical method. It is noteworthy to mention that the nanomaterials prepared via ultra-sonication exhibit porous nanostructure and porous structure [31, 32] . In addition, the preparations of nanomaterials based on sonochemical approach are free from toxic solvents and easy to manipulate [33-35]. As rationale inspired by these facts, an economic and artful electrochemical nanosensor was proposed for simultaneous voltammetric analysis of daclatasvir (DAC) and hydroxychloroquine (HCQ) in human plasma and urine samples for the first time. The sensor based on the synthesis of zinc sulfide nanoparticles/reduced graphene oxide (ZnS NPs@ rGO) by sonochemical technique. The main advantages of the proposed sensor are simplicity, sensitivity, reliability and selectivity, while the main disadvantage is inability to determine these analytes in presence of chloroquine. Daclatasvir was obtained as a gift from NODCAR, El-Dokki, Giza, Egypt. Hydroxychloroquine sulfate, Graphene oxide, hydrazine, uric acid, methionine, cysteine, adenine, guanine, glutathione were purchased from Sigma Aldrich. Glucose, Potassium permanganate, ethanol, sodium nitrate, hydrochloric acid, acetonitrile, ferrocyanide, ferricyanide, boric acid, phosphoric acid, sodium sulfide, zinc chloride were purchased from El-Nasser Intermediate for Chemicals, Cairo, Egypt. 2.5 mL of urine sample (from healthy volunteers) was centrifuged at 1500 rpm for 20 min. Then, the urine sample was filtered using 0.45 mm filter paper and 0.5 mL of the supernatant was transferred to voltammetric sample containing phosphate buffer (pH=6.0). 0.5 mL Human plasma was mixed with 1.0 mL ACN and subjected to centrifugation to about 30 min to remove possible interference. After that, the supernatant was collected and diluted with 5 mL phosphate buffer (pH= 6.0) prior to the voltammetric analysis [36]. Graphite oxide (GO) was synthesized from natural graphite by modified Hummers method. Then, 50 mg of the synthesized GO was dispersed in water and ultrasonicated for 90 min. Then, 0.5 mM of ZnCl 2 and 0.25 mM of Na 2 S were added to the mixtures under stirring before addition of 30 mL of ethylene glycol. The final mixture was allowed in ultrasonic water bath (50 kHz frequency and 60 W) for 30 min. After that, the final product was centrifuged at 4000 rpm and 7 3. Results and discussions The waves produced by the sonicator generate tiny and highly energetic vapor filled bubbles that upon implosive collapse can create more microjets, locally high temperature and pressure. These formed microbubbles make ZnS NPs to move from the bulk solution to the surfaces of rGO nanosheets. Moreover, the hydrodynamic interaction of microbubbles with the mixed solutions improves the dispersion of nanoparticles on the surface of rGO and prevents their aggregations [37, 38] . It was found that the nanoparticles produced by the chemical sonication would have lower particle sizes (25-30 nm) than untreated ones (50-60 nm). Metal sulfides have more interest and considerable attention for its unique properties like chemical stability, low cost, less-toxicity, catalytic ability and thermal stability [39, 40] . Therefore, it has significant applications in various fields including supercapacitors, water splitting reactions, batteries, dye-sensitized solar cells, drug delivery, photo and electro-catalysis [41, 42] . Unfortunately, metal sulfides tend to aggregate [43] . As a result, integrating metal sulfides and high conductive matrix into a nanostructure has been demonstrated as a valuable approach to improve the conductivity and non-aggregativity of the nanocomposite [44] . Reduced graphene oxide nanosheets (rGOs) are novel layered materials that possess high conductivity and large electro-catalytic sites or surface areas and have various applications [45, 46] . In addition, rGOs are more interacted with metal sulfides and its one kind of electrostatic interaction of two nanomaterials [47, 48] . The morphology and composition of ZnS NPs@rGO were investigated using different techniques. Fig.S2a NPs@rGO where it shows two main peaks at 1355 cm -1 and 1630 cm -1 , which correspond to D and G bands, respectively. The D and G bands are assigned to the out-of-plane vibration (A1g symmetry) and in-plane vibration (E2g mode) of sp 2 -bonded carbon atoms [55] . In comparison to pristine GO, the Raman spectrum of ZnS NPs@rGO shows ID/IG intensity (1.25) is higher than pristine GO (0.92). Moreover, ZnS NPs@rGO nanocomposite shows small band at 311.5 cm -1 , corresponding to Cu-S stretching. The porous structures and surface areas of ZnS NPs and ZnS NPs@rGO nanomaterials were evaluated by BET analysis (Fig.S7 ). According to IUPAC classification, the isotherms of both exhibited type IV Hysteresis, which indicates mesoporous nature of them [56] . The measured BET surface areas are 14.67 m 2 g βˆ’1 and 87.67 m 2 g βˆ’1 for ZnS NPs and ZnS NPs@rGO, respectively. The electro-catalytic behavior of ZnS NPs@rGO was studied using CV and EIS as seen in The electrochemical oxidation of HCQ and DAC at ZnS NPs@rGO/GCE were affected by pH of the medium. The effect of different pH values in the range of 4.5 to 7.0 was investigated and illustrated in Fig.2 . The ZnS NPs@rGO/GCE shows oxidation peaks responses were gradually changed upon increasing the pH value. Markedly, the oxidation peaks potentials of HCQ and DAC were shifted to negative direction upon increasing the pH value, suggesting contribution the protons within the oxidation mechanism [57, 58] . In addition, the maximum peak currents for both HCQ and DAC were obtained at pH 5.5. As a result, pH 5.5 was chosen as an optimum value for simultaneous measurement of HCQ and DAC in their combined mixture. The oxidation peak currents were reduced with increasing pH due to the pKa values of DAC and HCQ, which are 6.09 and 4.0 [59, 60] . Moreover, in highly acidic pH ZnS NPs can be oxidized to Zn 2+ ; while between rGO and ZnS NPs would decrease. Based on these evidences, the pH 5.5 was chosen as an optimum value for simultaneous analysis of DAC and HCQ. Step height, pulse height, pulse width and pulse period were measured in the range of 0.05-0. The ZnS NPs@rGO/GCE combined with DVP under the optimized conditions in B.R. buffer (pH=5.5). The stripping peaks presented a good peak potential separation (more than 0.35 V), which allows the simultaneous analysis of HCQ and DAC. Initially, the concentration of HCQ was increased linearly in presence of fixed concentration of DAC (Fig.3A ) and vice versa (Fig.3B) .These results confirmed that the change concentration of one compound did not affect the stripping currents of another compound, indicating that their responses are independent. Secondly, both HCQ and DAC were determined simultaneously by increasing their concentrations (Fig. 3C) . The results of calibration plots were summarized in Table 1 . It is clearly observed that the values were almost identical for both molecules under optimum conditions of measurement. In addition, the analytical parameters such as linear range and LOD were compared with the previously reported methods for the analysis of HCQ and DAC ( Table 2 ). It can be seen that the proposed electrode has a better electro-catalyst activity than the previously reported methods. Hence, the modified electrode is more suitable for analysis of HCQ and DAC either individually or simultaneously. Reproducibility of the proposed method was studied by measuring the same sample mixture with three different electrodes of the same composition (n=3). The RSDs % values for HCQ and DAC were found to be 3.5 % and 3.2 % for HCQ and DAC, respectively. On the other hand, the repeatability was measured by measuring the sample mixture under the same experimental conditions at n=5 (in the same day) and the RSDs % values were found to be 1.6% and 1.9% for HCQ and DAC, respectively. The stability of the ZnS NPs@rGO modified GCE was investigated using DPV method at room temperature for simultaneous analysis of HCQ and DAC. The modified electrode retained about 95.89% from its initial activity over 50 cycles (Fig. S11a ). This indicates that the modified sensor has good stability due to its content of rGO, which has robust mechanical stability [69] . Moreover, the modified electrode was used for measurement of HCQ and DAC simultaneously for 30 days. It was found that the proposed electrode kept about 96.45% from its initial sensitivity for 25 days (S11b). Furthermore, the stability of the modified electrode was tested before and after analysis and slight variation was seen in the diffraction peaks of ZnS NPs that may be attributed to the oxidation of 2.27% of ZnS to ZnO (Fig.S12 ). The effect of potentially interfering compounds such as ascorbic acid (AA), uric acid (UA), glucose (GlC), dopamine (DA), glutathione (GLU), Ca 2+ , Mg 2+ , Na + , K + , adenine (Aden), guanine (Gua) and methionine (Meth) was evaluated using 50 nM HCQ and DAC (Fig.S13) . It was found that 600 fold of Ca 2+ , Mg 2+ , Na + , K + ; 450 fold AA, UA, GLC, DA,GLU, Meth; and 400 fold Aden and Gua not affect the anodic potentials and currents of HCQ and DAC (relative errors not exceed 5%). This means that the proposed method can be applied with high reliability for analysis of HCQ and DAC in biological samples. The analytical applicability of ZnS NPs@rGO/GCE was evaluated by detecting of HCQ and DAC in human plasma and urine samples. The results for detection of HCQ and DAC by standard addition method are cited in Table 3 . The samples were analyzed by HPLC method, and it was found that no significant difference between the proposed and HPLC methods. Consequently, the proposed sensor is accurate enough for HCQ and DAC assay in plasma and urine samples. Herein, a simple one pot sonochemical method was proposed for fabrication of ZnS NPs modified rGO. The nanocomposite was characterized using different methods, and used for simultaneous analysis of HCQ and DAC with good selectivity. The ZnS NPs/ rGO showed nanomolar detection of HCQ and DAC with good accuracy and precision. The proposed electrode exhibits some advantages such as high selectivity, sensitivity, reproducibility and stability. The higher electrochemical activity of the electrode may be attributed to fast electron transfer, high effective surface area and good conductivity. It was used for determination of the cited drugs in real biological fluids with satisfactory results. Therefore, the ZnS NPs/ rGO modified GCE opens a new venue for its applications as the electrochemical sensor to detect multiple drugs in their matrices. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 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