Safety and tolerability of Sacubitril/Valsartan in heart failure patient with reduced ejection fraction.

BACKGROUND: Angiotensin receptor blocker and a neprilysin inhibitor (ARNI) has emerged as an innovative therapy for patients of heart failure with reduced ejection fraction (HFrEF). The purpose of this study was to assess the safety and tolerability of Sacubitril/Valsartan in patient with HFrEF in Pakistani population. METHODS: This proof-of-concept, open label non-randomized clinical trial was conducted at a tertiary care cardiac center of Karachi, Pakistan. Patients with HFrEF were prescribed with Sacubitril/Valsartan and followed for 12 weeks for the assessment of safety and tolerability. Safety measures included incidence of hypotension, renal dysfunction, hyperkalemia, and angioedema. RESULTS: Among the 120 HFrEF patients, majority were male (79.2%) with means age of 52.73 ± 12.23 years. At the end of 12 weeks, four (3.3%) patients died and eight (6.7%) dropped out of the study. In the remaining 108 patients, 80.6% (87) of the patients were tolerant to the prescribed dose. Functional class improved gradually with 75.0% (81) in class I and 24.1% (26) in class II, and only one (0.9%) patient in class III at the end of 12 weeks. Hyperkalemia remains the main safety concern with incidence rate of 21.3% (23) followed by hypotension in 19.4% (21), and renal dysfunction in 3.7% (4) of the patients. CONCLUSIONS: Sacubitril/Valsartan therapy in HFrEF patients is safe and moderately tolerated among the Pakistani population. It can be used as first line of treatment for these patients. TRIAL REGISTRATION: NCT05387967. Registered 24 May 2022-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT05387967.

Discovery of novel 4,5-diphenyl-imidazol-α-aminophosphonate hybrids as promising anti-diabetic agents: Design, synthesis, in vitro, and in silico enzymatic studies.

Herein, a novel series of 4,5-diphenyl-imidazol-α-aminophosphonate hybrids 4a-m was designed, synthesized, and evaluated as new anti-diabetic agents. These compounds were evaluated against two important target enzymes in the diabetes treatment: α-glucosidase and α-amylase. These new compounds were synthesized in three steps and characterized by different spectroscopic techniques. The in vitro evaluations demonstrated that all the synthesized compounds 4a-m were more potent that standard inhibitor acarbose against studied enzymes. Among these compound, the most potent compound against both studied enzymes was 3-bromo derivative 4l. The latter compound with IC50 = 5.96 nM was 18-times more potent than acarbose (IC50 = 106.63 nM) against α-glucosidase. Moreover, compound 4l with IC50 = 1.62 nM was 27-times more potent than acarbose (IC50 = 44.16 nM) against α-amylase. Molecular docking analysis revealed that this compound well accommodated in the binding site of α-glucosidase and α-amylase enzymes with notably more favorable binding energy as compared to acarbose.

Ethyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate in the smiles rearrangement reaction: straightforward synthesis of amino acid derived quinolin-2(1H)-one enamines.

This paper describes the development of 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate compound as a heterocyclic enols containing a Michael acceptor so that it participates in an Ugi-type multicomponent condensation through a Smiles rearrangement in replacement of acid components. The new four-component containing 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate, aldehyde derivatives, amine derivatives and isocyanides process leads readily and efficiently to heterocyclic enamines. This report is an outstanding strategy for the preparation of new biologically structures containing peptidic or pseudo-peptidic with quinolin-2(1H)-one scaffolds.

Ugi Bis-Amide Derivatives as Tyrosinase Inhibitor; Synthesis, Biology Assessment, and in Silico Analysis.

Herein, a straightforward synthetic strategy mediated by Ugi reaction was developed to synthesize novel series of compounds as tyrosinase inhibitors. The structures of all compounds were confirmed by FT-IR, 1 H-NMR, 13 C-NMR, and CHNOS techniques. The tyrosinase inhibitory activities of all synthesized derivatives 5a-m were determined against mushroom tyrosinase and it was found that derivative 5c possesses the best inhibition with an IC50 value of 69.53±0.042 µM compared to the rest of the synthesized derivatives. Structure-activity relationships (SARs) showed that the presence of 4-MeO or 4-NO2 at the R2 position plays a key role in tyrosinase inhibitory activities. The enzyme kinetics studies showed that compound 5c is an noncompetitive inhibitor. For in silico study, the allosteric site detection was first applied to find the appropriate binding site and then molecular docking and molecular dynamic studies were performed to reveal the position and interactions of 5c as the most potent inhibitor within the tyrosinase active site. The results showed that 5c bind well with the proposed binding site and formed a stable complex with the target protein.

Impact of domestic and industrial effluent on marine environment at Karachi Port Trust (KPT) coastal area, Pakistan.

The extent of aquatic pollution of Karachi Port Trust (KPT) coastal area located at the south of Pakistan coast has increased considerably in the last few decades due to unrestricted discharge of sanitary waste. The current study lays emphasis on the identification of vulnerable zones severely impacted by pollution in the KPT coastal area using laboratory monitoring, geospatial techniques, and statistical analysis. During 2019, sampling was conducted along the KPT coastal area, and 54 samples of seawater were collected during pre- and post-monsoon seasons. The outcomes of physical and chemical analysis revealed that the concentrations of BOD (biochemical oxygen demand), COD (chemical oxygen demand), nitrate, phosphate, phenol, cyanide, and oil and grease frequently exceeded the permitted limit of international norms and reached much greater levels. The levels of perilous metals in the seawater samples were in the order Ni>Cr>Cu>Pb>Cd>As in both phases and also reached to elevated levels as a consequence of the indiscriminate discharge of untreated industrial and domestic wastewater. Based on detailed examination during pre- and post-monsoon, six sites near KPT, Lyari River outfall, and Karachi Harbour were identified as highly polluted zones due to heavy discharge of sanitary effluents at these sites. In particular, the industrial zones present in the formal and informal sectors of Karachi are responsible for the deterioration of the KPT coastal area. Therefore, it is advised to design and build a submerged drainage system to transport and distribute massive amounts of treated municipal and industrial waste to the deep open sea in order to minimize the high pollutant levels in these locations.

A Conformationally Stable Acyclic ß-Hairpin Scaffold Tolerating the Incorporation of Poorly ß-Sheet-Prone Amino Acids.

The ß-hairpin is a structural element of native proteins, but it is also a useful artificial scaffold for finding lead compounds to convert into peptidomimetics or non-peptide structures for drug discovery. Since linear peptides are synthetically more easily accessible than cyclic ones, but are structurally less well-defined, we propose XWXWXpPXK(/R)X(R) as an acyclic but still rigid ß-hairpin scaffold that is robust enough to accommodate different types of side chains, regardless of the secondary-structure propensity of the X residues. The high conformational stability of the scaffold results from tight contacts between cross-strand cationic and aromatic side chains, combined with the strong tendency of the d-Pro-l-Pro dipeptide to induce a type II' ß-turn. To demonstrate the robustness of the scaffold, we elucidated the NMR structures and performed molecular dynamics (MD) simulations of a series of peptides displaying mainly non-ß-branched, poorly ß-sheet-prone residues at the X positions. Both the NMR and MD data confirm that our acyclic ß-hairpin scaffold is highly versatile as regards the amino-acid composition of the ß-sheet face opposite to the cationic-aromatic one.

Dual Role of Oxoaldehydes: Divergent Synthesis of 3-Aryl- and 3-Aroylcoumarins.

A facile and efficient synthetic approach to various valuable 3-aryl- and 3-aroylcoumarins by the direct arylation and aroylation of coumarins with glyoxals in a metal-free manner is presented. The aryl glyoxal is for the first time recognized to serve as an aryl surrogate in addition to its role as an aroyl transfer reagent via a simple switch in reaction conditions. The approach accommodates a broad substrate scope and high yields of the two types of cross-coupling reactions starting from identical starting materials.

Backbone distortions in lactam-bridged helical peptides.

Side-chain-to-side-chain cyclization is frequently used to stabilize the α-helical conformation of short peptides. In a previous study, we incorporated a lactam bridge between the side chains of Lys-i and Asp-i+4 in the nonapeptide 1Y, cyclo-(2,6)-(Ac-VKRLQDLQY-NH2 ), an artificial ligand of the inhibitor of DNA binding and cell differentiation (ID) protein with antiproliferative activity on cancer cells. Herein, we show that only the cyclized five-residue segment adopts a helical turn whereas the C-terminal residues remain flexible. Moreover, we present nine 1Y analogs arising from different combinations of hydrophobic residues (leucine, isoleucine, norleucine, valine, and tyrosine) at positions 1, 4, 7, and 9. All cyclopeptides except one build a lactam-bridged helical turn; however, residue-4 reveals less helix character than the neighboring Arg-3 and Gln-5, especially with residue-4 being isoleucine, valine, and tyrosine. Surprisingly, only two cyclopeptides exhibit helix propagation until the C-terminus, whereas the others share a remarkable outward tilting of the backbone carbonyl of the lactam-bridged Asp-6 (>40° deviation from the orientation parallel to the helix axis), which prevents the formation of the H-bond between Arg-3 CO and residue-7 NH: As a result, the propagation of the helix beyond the lactam-bridged sequence becomes unfavorable. We conclude that, depending on the amino-acid sequence, the lactam bridge between Lys-i and Asp-i+4 can stabilize a helical turn but deviations from the ideal helix geometry are possible: Indeed, besides the outward tilting of the backbone carbonyls, the residues per turn increased from 3.6 (typical of a regular α-helix) to 4.2, suggesting a partial helix unwinding.

Evaluating the effects of disubstituted 3-hydroxy-1H-pyrrol-2(5H)-one analog as novel tyrosinase inhibitors.

In the present study, a series of 3-hydroxy-1H-pyrrol-2(5H)-one derivative were rationally designed and synthesized. The structure of targeted compounds was confirmed by IR, 1H NMR, 13C NMR, and elemental analysis. Next, all derivatives were evaluated as tyrosinase inhibitors, and among the synthesized derivatives, compound 6a was proved to be the most potent inhibitor with an IC50 value of 6.98 ± 1.05 µM. Kinetic study of compound 6a confirmed the mixed type of inhibitory activity towards tyrosinase. Furthermore, the results of the molecular docking study showed that this compound fitted well in the active site of tyrosinase and exhibited interaction with important residues of the binding site.

Design, Synthesis, in Vitro, and in Silico Evaluation of N-Phenylacetamide-Oxindole-Thiosemicarbazide Hybrids as New Potential Tyrosinase Inhibitors.

A novel series of N-phenylacetamide-oxindole-thiosemicarbazide hybrids were synthesized and evaluated for their tyrosinase inhibitory activity. According to tyrosinase inhibition results, all the synthesized compounds showed high tyrosinase inhibitory activity with IC50 values ranging from 0.8 to 3.88 µM in comparison to positive control kojic acid with IC50 value of 36.32 µM. Among tested compounds, analog 7o, containing the 2-methyl-4-nitrophenyl on N-phenylacetamide moiety displayed superior tyrosinase inhibition. This compound was around 45-fold more potent than kojic acid. The kinetic analysis of compound 7o demonstrated that this compound is a competitive inhibitor against tyrosinase. Docking study of this compound demonstrated that compound 7o interacted with critical histidine residues within tyrosinase active site.

Evaluating dual exposure by using climate-conflict vulnerability index on the coastal districts of Sindh, Pakistan.

Climate variability is widely recognized as a major concern, particularly in resource-scarce regions where it limits livelihood opportunities by putting additional strain on already depleting resources, resulting in human insecurity and conflicts. Some vulnerability assessments have created a nexus between climate variability and conflicts. The Climate-Water Conflict Vulnerability Index (CWCVI) and the Climate-Agriculture Conflict Vulnerability Index (CACVI) are applied as a tool for exploring the climate and conflict interactions, as well as contrasting the vulnerabilities of the coastal districts of Badin, Thatta, and Sujawal. The analysis incorporates a dual exposure of communities in the form of climate variability and conflict over water and agricultural resources. The study finds that aggression and feelings of insecurity about depleting resources are the main contributing indicators of climate-conflict vulnerability in the coastal districts. District Sujawal showed higher vulnerability in adaptive capacity as compared to the other districts due to poor infrastructure and high dependency on natural resources. However, the district of Badin demonstrated high vulnerability in terms of sensitivity and its exposure to conflicts over agricultural resources is high. The overall CWCVI and CACVI scores were higher in Badin and Thatta, respectively. This study identifies a number of indicators that can be used to improve the efficacy of mitigation strategies to reduce conflict vulnerability in future policy directions and resource planning.

Geospatial assessment of water quality using principal components analysis (PCA) and water quality index (WQI) in Basho Valley, Gilgit Baltistan (Northern Areas of Pakistan).

Public health quality in Gilgit Baltistan (GB) is at threat due to multiple water-borne diseases. Anthropogenic activities are accelerating the burden of pollution load on the glacio-fluvial streams and surface water resources of Basho Valley in Skardu district of GB. The present research has investigated the drinking water quality of the Basho Valley that is being used for domestic purposes. The study also comprehends public health status by addressing the basis drinking water quality parameters. A total of 23 water samples were collected and then analyzed to elucidate the current status of physico-chemical, metals, and microbial parameters. Principal component analysis (PCA) was applied and three principal components were obtained accounting 53.04% of the total variance, altogether. PCA identified that metallic and microbial parameters are the major factor to influence the water quality of the valley. Meanwhile, water quality index (WQI) was also computed and it was observed that WQI of the valley is characterized as excellent in terms of physico-chemical characteristics; however, metals and microbial WQI shows most of the samples are unfit for drinking purpose. Spatial distribution is also interpolated using the Inverse distance weight (IDW) to anticipate the results of mean values of parameters and WQI scores. The study concludes that water quality is satisfactory in terms of physico-chemical characteristics; however, analysis of metals shows that the concentrations of copper (Cu) (0.40 ± 0.16 mg/L), lead (Pb) (0.24 ± 0.10 mg/L), zinc (Zn) (6.77 ± 27.1 mg/L), manganese (Mn) (0.19 ± 0.05), and molybdenum (Mo) (0.07 ± 0.02 mg/L) are exceeding the maximum permissible limit as set in the WHO guidelines for drinking water. Similarly, the results of the microbial analysis indicate that the water samples are heavily contaminated with fecal pollution (TCC, TFC, and TFS > 3 MPN/100 mL). On the basis of PCA, WQI, and IDW, the main sources of pollution are most likely to be concluded as the anthropogenic activities including incoming pollution load from upstream channels. A few underlying sources by natural process of weathering and erosion may also cause release of metals in surface and groundwater. This study recommends ensuring public health with regular monitoring and assessment of water resources in the valley.

Addressing COVID-19 contagion through the HVAC systems by reviewing indoor airborne nature of infectious microbes: Will an innovative air recirculation concept provide a practical solution?

As the world continues to grapple with the reality of coronavirus disease, global research communities are racing to develop practical solutions to adjust to the new challenges. One such challenge is the control of indoor air quality in the COVID-19 era and beyond. Since COVID-19 became a global pandemic, the "super spread" of the virus has continued to amaze policymakers despite measures put in place by public health officials to sensitize the general public on the need for social distancing, personal hygiene, etc. In this work, we have reviewed the literature to demonstrate, by investigating the historical and present circumstances, that indoor spread of infectious diseases may be assisted by the conditions of the HVAC systems. While little consideration has been given to the possibility of indoor airborne transmission of the virus, the available reports have demonstrated that the virus, with average aerodynamic diameter up to 80-120 nm, is viable as aerosol in indoor atmosphere for more than 3 h, and its spread may be assisted by the HVAC systems. Having reviewed the vulnerability of the conventional ventilation systems, we recommend innovative air circulation concept supported by the use of UVGI in combination with nanoporous air filter to combat the spread of SARS-CoV-2 and other harmful microbes in enclosed spaces.

Assessment of groundwater quality in the coastal area of Sindh province, Pakistan.

Groundwater is a highly important resource, especially for human consumption and agricultural production. This study offers an assessment of groundwater quality in the coastal areas of Sindh province in Pakistan. Fifty-six samples of groundwater were taken at depths ranging from 30 to 50 m. Bacteriological and physico-chemical analyses were performed using the Standard Methods for the Examination of Water and Wastewater. These were supplemented with expert interviews and observations to identify the usage of water and potential sources of pollution. The quality of the groundwater was found to be unsuitable for human consumption, despite being used for this purpose. The concentrations of sulfate and phosphate were well within the tolerance limits. Most critical were the high levels of organic and fecal pollution followed by turbidity and salinity. Metal concentrations (As, Ca, Cr, Cu, Fe, Mg, Mn, Ni, Pb, and Zn) were also determined, and Ni and Pb strongly exceeded health standards. The study stresses the need for significant improvements of the irrigation, sanitation, and sewage infrastructure.

Patterns And Determinants Of Breast Feeding Among Mother Infant Pairs In Dera Ghazi Khan, Pakistan.

BACKGROUND: Proper breastfeeding practices are effective ways for reducing childhood morbidity and mortality. The objective of the present study was to determine the patterns and explore the determinants associated with breast feeding practices among the nursing women in Dera Ghazi Khan. METHODS: A cross sectional study was conducted on randomly selected lactating mother infant pairs in Dera Ghazi Khan. Structured questionnaire was used for data collection. Analysis was done by using SPSS, chi square test was applied to see the association between breast feeding practices and its determinants such as knowledge of breast feeding practices. RESULTS: Majority 372 (93%) of mothers mentioned that they had ever breastfed the youngest child. About 292 (73%) mothers gave colostrum to the child, and 48 (12%) exclusively breastfed. Weaning babies before four month of age was practiced by 84 (21%) of the mothers, 120 (55%) mothers started weaning at 4-6 months of child age, while 72 (18%) started to give additional food after baby turned six months old. Out of total 276 (69%) mothers reported that they had knowledge regarding breast feeding. Significant association was found between knowledge of breastfeeding and initiation and Exclusive Breast Feeding (EBF) practices (p-values <0.05). Income, family type, mode of delivery and assistance for child were significantly associated with initiation of breastfeeding within one hour after birth (p-value <0.001). CONCLUSIONS: Breast feeding practices in the studied area were not up to the mark. There is a strong need to improve the breastfeeding practices by Behavior Change Communication.

Effect Of Sitagliptin On Glycemic Control, Body Weight, Blood Pressure And Serum Lipid Profile In Type 2 Diabetic Hyperlipidemic Patients.

BACKROUND: Dyslipidaemia is a global health issue in developed as well as in developing countries. People with type 2 Diabetes mellitus are more susceptible to develop dyslipidaemia and its related complications. The objective of the study was to assess the effect of sitagliptin a (DPP-4 inhibitor) oral antidiabetic drug on blood sugar, body weight, blood pressure and dyslipidaemia in type 2 diabetic patients. METHODS: This 12 weeks open label observational study was conducted at outdoor of diabetic clinic of Sheikh Zayed Medical College/Hospital, Rahim Yar Khan in which newly diagnosed type 2 diabetic patients (n=78) with poor glycaemic control(HbA1c >7.2%) were selected. The patient received sitagliptin 50 mg twice daily for 12 weeks. RESULTS: After 12 weeks treatment with sitagliptin, there was a significant reduction in the value of HbA1c from 8.184%±0.467 at baseline to 7.0200%±0.459 at 12 weeks (p<0.05). Body weight also decreased significantly from 80.21kg±7.156 at baseline to 71.74 kg±6.567 at 12 weeks (p<0.05).Systolic blood pressure decreased (SBP) decreased significantly from 138.17±6.050 mmHg at baseline to 131.22±6.311 mmHg at 12 weeks (p<0.05). Significant changes were also seen in diastolic blood pressure which decreased from 83.14±6.714 mmHg at baseline to 75.28±6.481 mmHg at 12 weeks (p<0.05). Significant reduction in the serum level of total Cholesterol (TC), triglycerides (TG) and Low density lipoprotein cholesterol (LDL-C) were detected (TC: 222.09±13.538 to 209.41±13.475 mg/dl, p<0.05; TG: 170.99±6.940 to 143.45±8.279 mg/dl, p<0.05; LDL-C 120.00±5.804 to 109.06±6.278 mg/dl, p<0.05). High density lipoprotein cholesterol (HDL-C) increased significantly from 42.99±4.836 mg/dl at baseline to 49.97±3.490 mg/dl at 12 weeks. CONCLUSIONS: Sitagliptin not only improves blood glucose control but also body weight, blood pressure and lipid profile in type 2 diabetic hyperlipidaemia patients.

Beneficial effects of sitagliptin and metformin in non-diabetic hypertensive and dyslipidemic patients.

Obesity, dyslipidemia and hypertension are major risk factors for cardiovascular disease and its associated complications. To evaluate the beneficial effects of sitagliptin and metformin in non-diabetic dyslipidemic and hypertensive patients. A prospective randomized clinical trial was conducted on 70 newly diagnosed dyslipidemic patients with BMI > 25 and blood pressure > 130/80 at outpatient clinic of medical unit-1 of Sheikh Medical College/Hospital, Rahim Yar Khan. They were divided in to three groups each containing 35 patients; First group served as a healthy control while second and third study groups were given tablet sitagliptin 50mg and tab metformin 850mg respectively twice a day for twelve weeks. After three months treatment with sitagliptin and metformin there was significant reduction in body weight (Sitagliptin 6.5% vs Metformin 7.65%) and BMI (Sitagliptin 2.2% vs Metformin 2.8%) with p <0.05. Metformin caused a significant reduction in blood pressure with p < 0.05 (i.e. SBP 9.9% & DBP 6.4%) while sitagliptin caused a highly significant p <0.01 reduction in blood pressure (i.e. SBP 15.8% & DBP 12.2%). There was significant improvement in lipid profile with sitagliptin p<0.05. The percent reduction in value of TC, TG and LDL-C was 20.2%, 13.8% and 23.7% while HDL-C value was increased 11.2% respectively. There was highly significant improvement in lipid profile with metformin p<0.01. The percent reduction in value of TC, TG and LDL-C was 27.8%, 28.2% and 40.4% while HDL-C value was increased 16.8% respectively. Both drugs improve cardiometabolic risk factors independently in non-diabetic patients.

Aryl-quinoline-4-carbonyl hydrazone bearing different 2-methoxyphenoxyacetamides as potent α-glucosidase inhibitors; molecular dynamics, kinetic and structure-activity relationship studies.

Regarding the important role of α-glucosidase enzyme in the management of type 2 diabetes mellitus, the current study was established to design and synthesize aryl-quinoline-4-carbonyl hydrazone bearing different 2-methoxyphenoxyacetamide (11a-o) and the structure of all derivatives was confirmed through various techniques including IR, 1H-NMR, 13C-NMR and elemental analysis. Next, the α-glucosidase inhibitory potentials of all derivatives were evaluated, and all compounds displayed potent inhibition with IC50 values in the range of 26.0 ± 0.8-459.8 ± 1.5 µM as compared to acarbose used as control, except 11f and 11l. Additionally, in silico-induced fit docking and molecular dynamics studies were performed to further investigate the interaction, orientation, and conformation of the newly synthesized compounds over the active site of α-glucosidase.

Geospatial quality assessment of locally available ice for heavy metals and metalloids and their potential risks for human health in Karachi, Pakistan.

Extreme hot conditions during summers, high poverty rate and continuous electricity load shedding affect commercial manufacturing and sale of ice in many countries. The vendors prepared ice using untreated piped water, tanker water and ground water. These waters may contain hazardous pollutants and ice made from them will pose a potential human health risk. Thus, it is important to regularly monitor the chemical composition of water sources and the quality of the manufactured ice. A contemporary examination was carried out to evaluate the physico-chemical properties and heavy metals and metalloids in the ice sold in all the districts of Karachi, Pakistan. This pioneering study was an innovative effort to assess the ice quality in relation to potential pollutant hazards to human health; with concomitant geospatial information. The geospatial distribution of ice quality and major constituents were among the measured parameters; carefully associated with further geospatial information, determined using GIS (Geographic Information Systems) and PCA (Principal Component Analysis) techniques. Interestingly, the physico-chemical analyses revealed that the ice quality was marginally adequate and the total mean metal-metalloid contents were in the sequence of Pb > Ni > Zn > Fe > Cr > As. The concentrations of these metals were above the upper allowable limits with reference to the recommended WHO guidelines. We observed that 57.1% and 35.7% ice samples had good physico-chemical properties assessed using the Ice Quality Index (IQI). Conversely, the IQI for metals showed that the ice was unsafe for human consumption. In terms of health risk assessment, the overall mean CDI (Chronic Daily Intake) and HQ (Hazard Quotient) values were in the order of Pb () > Ni (3.2) > Zn (2.3) > Fe (2.1) > Cr (1.6) > As (0.5) and Pb (7.4) > As (1.7) > Cr (0.5) > Ni (0.4 > Zn (0.008) > Fe (0.003), respectively. This study highlighted that routine monitoring of the water supplies available for making ice is required to protect public health.

Structure-based drug discovery and antimicrobial activity of ciprofloxacin-grafted Ugi adducts.

A new series of ciprofloxacin-derived Ugi adducts were rationally designed and synthesized. The synthesized molecules were explored for their potential antimicrobial activities against four pathogenic microorganisms. Among these derivatives, compound 7h with a 4-nitrophenyl substituent at R2 exhibited significant activity against two tested Gram-positive bacteria with a minimum inhibitory concentration value of 0.097 µg/mL while 7i bearing 4-chlorophenyl pendant demonstrated the best antimicrobial activities against Gram-negative bacteria. Furthermore, the analysis of the structure-activity relationships disclosed that types of substitutions differently affect the bacteria so the most potent derivative against Gram-negative infections was the least active one in Gram-positive microorganisms. Also, the molecular docking and molecular dynamic simulations were executed on 7i as the most potent Gram-negative anti-bacterial agent against ATP-binding sites of DNA gyrase B. Accordingly, our findings suggest that ciprofloxacin-based Ugi adducts are an interesting precursor for the design of potent antimicrobial agents.Communicated by Ramaswamy H. Sarma.