Retracted Article: Boric acid in magnetized water: clean and powerful media for synthesis of 3,4-dihydropyrimidin-2(1H)-ones

Water was magnetized via an external magnetic field and employed, for the first time, as a solvent in green preparation of 3,4-dihydropyrimidin-2(1H)-ones by the one-pot three-component condensation reaction using boric acid as a catalyst. Shorter reaction times, higher yields, and cleaner reaction profiles were some advantages of using magnetic water.

Water was magnetized via an external magnetic field and employed, for the first time, as a solvent in green preparation of 3,4-dihydropyrimidin-2(1H)-ones by the one-pot three-component condensation reaction using boric acid as a catalyst.

It is well-known that water is the most crucial matter in nature, thus in numerous papers, physical and chemical properties of water and also their changes under actions of external factors like electromagnetic fields have been investigated,¹ although the principle of magnetic field (MF) treatment on the water is still a controversial subject, and no clear mechanisms of this effect have been reported in the literature.² Many studies have indicated that the physicochemical properties of water change by passing through the MF,³ for example, inter- and intra-cluster hydrogen bonds, coagulation, polymorphism of the crystals, the zeta potential of the precipitated or dispersed particles, viscosity, diffusivity, surface tension, friction coefficient, pH values, electrical conductivity, and some physical properties of water, including specific heat, evaporation amount and boiling point.⁴ Owing to the changes in physicochemical properties, magnetic water has been utilized mainly for agriculture, wastewater treatment, industry, and construction.⁵ The magnetization of water and its effectiveness on the physical and chemical properties of water depends on several factors including, magnetization and exhibition of a magnetic field, magnetic gradient, Lorentz force, and magnetic memory.⁶ Three mechanisms have been proposed for how the magnetic field affects water particles: (I) the spontaneous formation and collapse of cationic metal colloidal units in the interaction of magnetism and water, which leads to increase sedimentation in water; (II) the change in polarization of the dissolved ions in the water, the shape and size of the hydration layer cause some variations in the water properties; and (III) due to the polarity of the water molecules, the magnetic field will directly affect the nature of the water molecules, the third mechanism is largely consistent with the experiments performed.⁷ Recently, few research groups such as Alabi, Zuniga, and Rodgers have started to examine the magnetic field effects on chemical reactions and their consequences in yield and rate of reaction or product distribution. It was considered that these effects might be performed via the radical pair mechanism.⁸Encouraged by previous works in the application of magnetic water, we decided to produce and employ magnetic water as a solvent in some interesting organic reactions.⁹ The multi-component condensation reactions are valuable protocols for synthesizing desired compounds in one step without the separation of any intermediates in organic chemistry.¹⁰ In this chemical strategy, some beneficial features are high yields, shorter reaction times, high atomic economy, and low waste materials and energy consumption.¹¹ So staying in this direction can bring us closer to the goals of green chemistry.¹² Preparation of 3,4-dihydropyrimidin-2(1H)-one (DHPMs) is significant due to their therapeutic and pharmacological properties, for example; Batzelladine, found in marine natural alkaloids, as an HIV inhibitor,^13a also monastrol,^13b and SQ 32926,^13c have been explained as synthetic or natural DHPs with biological properties (Scheme 1). The Biginelli reaction was reported for the first time by Pietro Biginelli.¹⁴ In this reaction, 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) were prepared by a three-component condensation reaction of aldehyde, urea, and β-ketoester as interesting compounds with a potential for pharmaceutical applications. Various catalysts were reported for this reaction such as, [bmim][MeSO₄],¹⁵ FeCl₃,¹⁶ RuCl₃,¹⁷ TMSCl,¹⁸ ZrSA¹⁹ and [H-NMP][CH₃SO₃].²⁰ Due to the important properties of these compounds, finding the new protocols for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones are still needed.Open in a separate windowScheme 1DHPMs containing natural or synthetic parts.Nowadays, many reactions need catalysts to carry out. Among many kinds of them, organocatalysts have attracted much attention. They are well-known as artificial catalysts for these plans. In comparison with inorganic catalysts and enzymes, they are not complicated, regularly less toxic, and widely available.²¹ Boric acid, as an organocatalyst, aqueous solution system, is one of the efficient and green catalytic systems in organic chemistry. Boric acid was successfully utilized in the preparation of different organic compounds such as, pyrano[2,3-d]pyrimidine diones,²² tetrahydrobenzo[b] pyrans,²³N,N′-alkylidene bisamides,²⁴ 4H-isoxazol-5-ones,²⁵ 2-arylamino-2-phenylacetamide,²⁶ bis(indolyl)methanes.²⁷ In these mild conditions, H⁺, which is abstracted from water by the interaction with B(OH)₃, efficiently catalyzes the reaction,^22,23 and water as a solvent plays a key role in these reactions. In water molecules, the non-uniform distribution of electrons leads to the creation of positive and negative particle charges. Based on points mentioned earlier, we wondered to evaluate the effect of magnetized water as a solvent and also using boric acid as a catalyst, on the synthesis of 3,4-dihydropyrimidin-2(1H)-one derivative (Scheme 2).Open in a separate windowScheme 2The one-pot three-component preparation of 3,4-dihydropyrimidin-2(1H)-ones in magnetized water/B(OH)₃ system.To prepare magnetic water, a cylindrical system with an approximate capacity of 100 mL was filled with neodymium super-magnets (Nd), which generated a magnetic field of 130 mT at the center and diameter of the tube, was used to construct the reactor of magnetic water. The water used in the system was distilled twice by the Prima30 machine and circulated in the system by a (SEBO P-280) pump with a power of 200 liters per hour, and after 8 hours, the water became magnetic. After the preparation of magnetic water, some main physicochemical properties, such as viscosity, gas solubility, refractive index, surface tension, pH, UV-visible and FT-IR analysis, were evaluated.Initially, the oxygen gas solubility in magnetic and ordinary water was measured by Winkler method based on standard method procedure.²⁸ After photometric testing, it was found that the solubility of oxygen in magnetic water was slightly higher than in ordinary water (MW : n-MW = 8 : 7 ppm). We suggested that probably the paramagnetism of oxygen structure, as well as the molecular orbital of oxygen, can be effective in presenting this result. A paramagnetic structure with magnetic properties is more soluble in a magnetized solvent.²⁹ Next, the viscosity, as an essential factor in the efficiency of organic reaction, was measured at different temperatures according to the reference method.³⁰ The results determined that the viscosity of magnetic water was generally slightly lower than ordinary distilled water. Based on our observations, it was found that the viscosity differences were higher at low temperatures, indicating that at high temperatures, the hydrogen bonds are almost weakened and results in no significant differences between the viscosity of magnetic water and ordinary water. In contrast, at low temperatures, because of the high number of intra-cluster bonds in ordinary water, they form a colloidal bulk structure that increases its viscosity. The intermolecular structure of the magnetic water molecules is hexagonal layers that are interconnected by inter-cluster hydrogen bonds, which form a graphite-like structure and gives a particular softness to the water and reducing its viscosity (Fig. 1a).³¹ This property could be effective in running the organic reaction. Moreover, the refractive index of magnetic water and nonmagnetic water was also evaluated by a refractometer at different temperatures. It was found that at low temperatures, the refractive index of magnetic water was approximately the same as distilled water, whereas, at higher temperatures, the refractive index of magnetic water was lower than ordinary water. To justify this observation, it can be noted that magnetic water has a more stable structure than ordinary water, and this somewhat stable structure limited waste fractures when the photons traveled through the water (Fig. 1b). Interestingly, our results were contrary to Hosoda et al. who showed magnetic water has a higher refractive index.³² They explained that it is because of the lifetime of the H-bonds. pH measurements can also be evaluated as a criterion for investigating hydrogen bond clusters. For this issue in mind, the pH changes of the water were measured at different temperatures. It was found that the acidity of the magnetic water was lower than ordinary water, and the difference between their pH enhanced with increasing temperature (Fig. 1c). Surface tension analysis for magnetized water and distilled water showed that ordinary water has a higher surface tension in different temperatures rather than magnetic water which was in good agreement with Cho''s report that magnetic field reduced the surface tension of natural water by about 8% (Fig. 1d).³³Open in a separate windowFig. 1The viscosity, refractive index, pH measurements, and surface tension analysis for magnetic and distilled water in different temperatures.Eventually, for examining the optical properties of magnetic and ordinary water, IR and UV analyses were performed. No significant difference was detected in the UV spectra (ESI, S1^†), but, interestingly, in the IR spectra, some peaks were weakened or disappeared, and some new peaks were observed (ESI, S2^†). There are two differences in comparing ordinary and magnetic water IR spectra: (I) the detection of Peaks 2923.53 and 2853.03 is probably due to internal structural patterns of H₂O molecules and/or hydrogen bond chain in ordinary water which in magnetic water these peaks are very weakened or not seen due to the new structural patterns of water molecules; (II) in the 1709.69 region, a new peak was detected in the magnetic water spectrum compared to ordinary water, which was attributed to the transition of the water phase from a complex irregular spherical structure to a regular hexagonal ring structure in magnetic water (Fig. 3).Open in a separate windowFig. 3Schematic diagram of the FTIR spectroscopy of magnetized and distilled water.After preparation and characterization of magnetic water, we wonder to investigate the preparation of 3,4-dihydropyrimidin-2(1H)-ones using boric acid, in nonmagnetic water and also magnetic water as solvent under reflux conditions. To find optimized conditions, we have chosen the reaction of ethyl acetoacetate (1 mmol), urea (1 mmol), and benzaldehyde (1 mmol) as a model reaction (

Antimalarial drug efficacy and resistance in malaria-endemic countries in HANMAT-PIAM_net countries of the Eastern Mediterranean Region 2016–2020: Clinical and genetic studies

Introduction

The World Health Organization recommends regular monitoring of the efficacy of nationally recommended antimalarial drugs. We present the results of studies on the efficacy of recommended antimalarials and molecular markers of artemisinin and partner resistance in Afghanistan, Pakistan, Somalia, Sudan and Yemen.

Methods

Single-arm prospective studies were conducted to evaluate the efficacy of artesunate-sulfadoxine-pyrimethamine (ASSP) in Afghanistan and Pakistan, artemether-lumefantrine (AL) in all countries, or dihydroartemisinin-piperaquine (DP) in Sudan for the treatment of Plasmodium falciparum. The efficacy of chloroquine (CQ) and AL for the treatment of Plasmodium vivax was evaluated in Afghanistan and Somalia, respectively. Patients were treated and monitored for 28 (CQ, ASSP and AL) or 42 (DP) days. Polymerase chain reaction (PCR)-corrected cure rate and parasite positivity rate at Day 3 were estimated. Mutations in the P. falciparum kelch 13 (Pfk13) gene and amplifications of plasmepsin (Pfpm2) and multidrug resistance-1 (Pfmdr-1) genes were also studied.

Results

A total of 1680 (249 for ASSP, 1079 for AL and 352 for DP) falciparum cases were successfully assessed. A PCR-adjusted ASSP cure rate of 100% was observed in Afghanistan and Pakistan. For AL, the cure rate was 100% in all but four sites in Sudan, where cure rates ranged from 92.1% to 98.8%. All but one patient were parasite-free at Day 3. For P. vivax, cure rates were 98.2% for CQ and 100% for AL. None of the samples from Afghanistan, Pakistan and Yemen had a Pfk13 mutation known to be associated with artemisinin resistance. In Sudan, the validated Pfk13 R622I mutation accounted for 53.8% (14/26) of the detected non-synonymous Pfk13 mutations, most of which were repeatedly detected in Gadaref. A prevalence of 2.7% and 9.3% of Pfmdr1 amplification was observed in Pakistan and Yemen, respectively.

Conclusion

High efficacy of ASSP, AL and DP in the treatment of uncomplicated falciparum infection and of CQ and AL in the treatment of P. vivax was observed in the respective countries. The repeated detection of a relatively high rate of Pfk13 R622I mutation in Sudan underscores the need for close monitoring of the efficacy of recommended ACTs, parasite clearance rates and Pfk13 mutations in Sudan and beyond. Registration numbers of the trials: ACTRN12622000944730 and ACTRN12622000873729 for Afghanistan, ACTRN12620000426987 and ACTRN12617001025325 for Pakistan, ACTRN12618001224213 for Somalia, ACTRN12617000276358, ACTRN12622000930785 and ACTRN12618001800213 for Sudan and ACTRN12617000283370 for Yemen.     

Retraction: Boric acid in magnetized water: clean and powerful media for synthesis of 3,4-dihydropyrimidin-2(1H)-ones

Retraction of ‘Boric acid in magnetized water: clean and powerful media for synthesis of 3,4-dihydropyrimidin-2(1H)-ones’ by Vahid Khakyzadeh et al., RSC Adv., 2021, 11, 22751–22755. DOI: 10.1039/D1RA03769B

We, the named authors, hereby wholly retract this RSC Advances article. Although we maintain that the results obtained in distilled water are accurate, and believe that further experiments will confirm our conclusions, following discussions between the authors and the Royal Society of Chemistry, we have determined that the evidence presented regarding magnetised water in this paper is insufficient to support the conclusions and needs further investigation. We are therefore retracting the paper to maintain the validity of the scientific record. The Royal Society of Chemistry apologises for the fact that these concerns were not identified during the peer review process.Signed: Vahid Khakyzadeh*^,a, Ahmad Reza Moosavi-Zare^b, Sahra Sheikhaleslami^a, Amir Ehsani^a, Salbin Sediqi^a, Mohammad Rezaei-Gohar^b and Zahra Jalilian^cDate: 27^th August 2021.Retraction endorsed by Laura Fisher, Executive Editor, RSC Advances, 27^th, August 2021.