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.

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.

Design, synthesis, in vitro, and in silico evaluations of kojic acid derivatives linked to amino pyridine moiety as potent tyrosinase inhibitors.

In the present study, novel series of kojic acid derivatives conjugated to amino pyridine moiety were designed and synthesized to explore their inhibitory activity against tyrosinase. To this end, the structure of all derivatives was characterized by 1H NMR, 13C NMR, FT-IR, and elemental analysis. Next, all derivatives were evaluated against tyrosinase compared to the kojic acid as positive control and exhibited different inhibitory potencies. Furthermore, the antioxidant potential of all derivatives was determined. The kinetic analysis of the most active agent revealed that 3-hydroxy-6-(hydroxymethyl)-2-((3-nitrophenyl)(pyridin-2-ylamino)methyl)-4H-pyran-4-one (4h) binds to the enzyme in the uncompetitive mode of action. The docking analysis and molecular dynamic simulations showed considerable binding affinity and significant interactions with tyrosinase enzyme to target the melanogenesis pathway, proposing them as potent candidates to control hyperpigmentation in the future.

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.

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.

Design, synthesis, in vitro, and in silico evaluations of benzo[d]imidazole-amide-1,2,3-triazole-N-arylacetamide hybrids as new antidiabetic agents targeting α-glucosidase.

α-Glucosidase as a carbohydrate-hydrolase enzyme is a crucial therapeutic target for type 2 diabetes. In this work, benzo[d]imidazole-amide containing 1,2,3-triazole-N-arylacetamide derivatives 8a-n were synthesized and evaluated for their inhibitory activity against α-glucosidase. In vitro α-glucosidase inhibition assay demonstrated that more than half of the title compounds with IC50 values in the range of 49.0-668.5 µM were more potent than standard inhibitor acarbose (IC50 = 750.0 µM). The most promising inhibitor was N-2-methylphenylacetamid derivative 8c. Kinetic study revealed that compound 8c (Ki = 40.0 µM) is a competitive inhibitor against α-glucosidase. Significantly, molecular docking and molecular dynamics studies on the most potent compound showed that this compound with a proper binding energy interacted with important amino acids of the α-glucosidase active site. Study on cytotoxicity of the most potent compounds 8c, 8e, and 8g demonstrated that these compounds did not show cytotoxic activity against the cancer and normal cell lines MCF-7 and HDF, respectively. Furthermore, the ADMET study predicted that compound 8c is likely to be orally active and non-cytotoxic.

Design, synthesis, in vitro anti-α-glucosidase evaluations, and computational studies of new phthalimide-phenoxy-1,2,3-triazole-N-phenyl (or benzyl) acetamides as potential anti-diabetic agents.

An important target in the treatment of type 2 diabetes is α-glucosidase. Inhibition of this enzyme led to delay in glucose absorption and decrease in postprandial hyperglycemia. A new series of phthalimide-phenoxy-1,2,3-triazole-N-phenyl (or benzyl) acetamides 11a-n were designed based on the reported potent α-glucosidase inhibitors. These compounds were synthesized and screened for their in vitro inhibitory activity against the latter enzyme. The majority of the evaluated compounds displayed high inhibition effects (IC50 values in the range of 45.26 ± 0.03-491.68 ± 0.11 µM) as compared to the positive control acarbose (IC50 value = 750.1 ± 0.23 µM). Among this series, compounds 11j and 11i represented the most potent α-glucosidase inhibitory activities with IC50 values of 45.26 ± 0.03 and 46.25 ± 0.89 µM. Kinetic analysis revealed that the compound 11j is a competitive inhibitor with a Ki of 50.4 µM. Furthermore, the binding interactions of the most potent compounds in α-glucosidase active site were studied through molecular docking and molecular dynamics. The latter studies confirmed the obtained results through in vitro experiments. Furthermore, in silico pharmacokinetic study of the most potent compounds was also performed.

Synthesis, in vitro α-glucosidase inhibitory activities, and molecular dynamic simulations of novel 4-hydroxyquinolinone-hydrazones as potential antidiabetic agents.

In the present study, new structural variants of 4-hydroxyquinolinone-hydrazones were designed and synthesized. The structure elucidation of the synthetic derivatives 6a-o was carried out using different spectroscopic techniques including FTIR, 1H-NMR, 13C-NMR, and elemental analysis, and their α-glucosidase inhibitory activity was also determined. The synthetic molecules 6a-o exhibited good α-glucosidase inhibition with IC50 values ranging between 93.5 ± 0.6 to 575.6 ± 0.4 µM as compared to the standard acarbose (IC50 = 752.0 ± 2.0 µM). Structure-activity relationships of this series were established which is mainly based on the position and nature of the substituent on the benzylidene ring. A kinetic study of the active compounds 6l and 6m as the most potent derivatives were also carried out to confirm the mode of inhibition. The binding interactions of the most active compounds within the active site of the enzyme were determined by molecular docking and molecular dynamic simulations.

Design, synthesis, and cytotoxic evaluation of quinazoline derivatives bearing triazole-acetamides.

A novel series of quinazoline-based agents bearing triazole-acetamides 8a-l were designed and synthesized. All the obtained compounds were tested for in vitro cytotoxic activities against three human cancer cell lines named HCT-116, MCF-7, and HepG2, as well as a normal cell line WRL-68 after 48 and 72 h. The results implied that quinazoline-oxymethyltriazole compounds exhibited moderate to good anticancer potential. The most potent derivative against HCT-116 was 8a (X = 4-OCH3 and R = H) with IC50 values of 10.72 and 5.33 µM after 48 and 72 h compared with doxorubicin with IC50 values of 1.66 and 1.21 µM, respectively. The same trend was seen in the HepG2 cancerous cell line in which 8a recorded the best results with IC50 values of 17.48 and 7.94 after 48 and 72 h, respectively. The cytotoxic analysis against MCF-7 showed that 8f with IC50 = 21.29 µM (48 h) exhibited the best activity, while compounds 8k (IC50 = 11.32 µM) and 8a (IC50 = 12.96 µM), known as the most effective cytotoxic agents after 72 h. Doxorubicin as positive control exhibited IC50 values of 1.15 and 0.82 µM after 48 and 72 h, respectively. Noteworthy, all derivatives showed limited toxicity against the normal cell line. Moreover, docking studies were also presented to understand the interactions between these novel derivatives and possible targets.

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.

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.

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.

Design, synthesis, in vitro, and in silico biological evaluations of coumarin-indole hybrids as new anti-α-glucosidase agents.

BACKGROUND: A series of coumarin-indole hybrids was synthesized as the new α-glucosidase inhibitors. The title hybrids were considered as α-glucosidase inhibitors because had two active pharmacophores against α-glucosidase: coumarin and indole. METHODS: The thirteen various derivatives 4a-m were synthesized, purified, and fully characterized. These compounds were evaluated against α-glucosidase in vitro and in silico. In silico pharmacokinetic studies of the most potent compounds were also performed. RESULTS: Most of the title compounds exhibited high anti-α-glucosidase activity in comparison to standard drug acarbose. In particular, the phenoxy derivative 4d namely 3-((1H-indol-3-yl)(3-phenoxyphenyl)methyl)-4-hydroxy-2H-chromen-2-one showed promising activity. This compound is a competitive inhibitor against α-glucosidase and showed the lowest binding energy at the α-glucosidase active site in comparison to other potent synthesized compounds and acarbose. CONCLUSION: Compound 4d can be a lead compound for further structural development to obtain effective and potent α-glucosidase inhibitors.

Docking study, molecular dynamic, synthesis, anti-α-glucosidase assessment, and ADMET prediction of new benzimidazole-Schiff base derivatives.

The control of postprandial hyperglycemia is an important target in the treatment of type 2 diabetes mellitus (T2DM). As a result, targeting α-glucosidase as the most important enzyme in the breakdown of carbohydrates to glucose that leads to an increase in postprandial hyperglycemia is one of the treatment processes of T2DM. In the present work, a new class of benzimidazole-Schiff base hybrids 8a-p has been developed based on the potent reported α-glucosidase inhibitors. These compounds were synthesized by sample recantations, characterized by 1H-NMR, 13C-NMR, FT-IR, and CHNS elemental analysis, and evaluated against α-glucosidase. All new compounds, with the exception of inactive compound 8g, showed excellent inhibitory activities (60.1 ± 3.6-287.1 ± 7.4 µM) in comparison to acarbose as the positive control (750.0 ± 10.5). Kinetic study of the most potent compound 8p showed a competitive type of inhibition (Ki value = 60 µM). In silico induced fit docking and molecular dynamics studies were performed to further investigate the interaction, orientation, and conformation of the title new compounds over the active site of α-glucosidase. In silico druglikeness analysis and ADMET prediction of the most potent compounds demonstrated that these compounds were druglikeness and had satisfactory ADMET profile.

Design and synthesis of new N-thioacylated ciprofloxacin derivatives as urease inhibitors with potential antibacterial activity.

A new series of N-thioacylated ciprofloxacin 3a-n were designed and synthesized based on Willgerodt-Kindler reaction. The results of in vitro urease inhibitory assay indicated that almost all the synthesized compounds 3a-n (IC50 = 2.05 ± 0.03-32.49 ± 0.32 µM) were more potent than standard inhibitors, hydroxyurea (IC50 = 100 ± 2.5 µM) and thiourea (IC50 = 23 ± 0.84 µM). The study of antibacterial activity against Gram-positive species (S. aureus and S. epidermidis) revealed that the majority of compounds were more active than ciprofloxacin as the standard drug, and 3h derivative bearing 3-fluoro group had the same effect as ciprofloxacin against Gram-negative bacteria (P. aeruginosa and E. coli). Based on molecular dynamic simulations, compound 3n exhibited pronounced interactions with the critical residues of the urease active site and mobile flap pocket so that the quinolone ring coordinated toward the metal bi-nickel center and the essential residues at the flap site like His593, His594, and Arg609. These interactions caused blocking the active site and stabilized the movement of the mobile flap at the entrance of the active site channel, which significantly reduced the catalytic activity of urease. Noteworthy, 3n also exhibited IC50 values of 5.59 ± 2.38 and 5.72 ± 1.312 µg/ml to inhibit urease enzyme against C. neoformans and P. vulgaris in the ureolytic assay.

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.

Synthesis, molecular docking, and cytotoxicity of quinazolinone and dihydroquinazolinone derivatives as cytotoxic agents.

BACKGROUND: Cancer is the most cause of morbidity and mortality, and a major public health problem worldwide. In this context, two series of quinazolinone 5a-e and dihydroquinazolinone 10a-f compounds were designed, synthesized as cytotoxic agents. METHODOLOGY: All derivatives (5a-e and 10a-f) were synthesized via straightforward pathways and elucidated by FTIR, 1H-NMR, CHNS elemental analysis, as well as the melting point. All the compounds were evaluated for their in vitro cytotoxicity effects using the MTT assay against two human cancer cell lines (MCF-7 and HCT-116) using doxorubicin as the standard drug. The test derivatives were additionally docked into the PARP10 active site using Gold software. RESULTS AND DISCUSSION: Most of the synthesized compounds, especially 5a and 10f were found to be highly potent against both cell lines. Synthesized compounds demonstrated IC50 in the range of 4.87-205.9 µM against HCT-116 cell line and 14.70-98.45 µM against MCF-7 cell line compared with doxorubicin with IC50 values of 1.20 and 1.08 µM after 72 h, respectively, indicated the plausible activities of the synthesized compounds. CONCLUSION: The compounds quinazolinone 5a-e and dihydroquinazolinone 10a-f showed potential activity against cancer cell lines which can lead to rational drug designing of the cytotoxic agents.

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.