Sulaiman Shams

Structural Basis of Binding and Rationale for the Potent Urease Inhibitory Activity of Biscoumarins

Urease belongs to a family of highly conserved urea-hydrolyzing enzymes. A common feature of these enzymes is the presence of two Lewis acid nickel ions and reactive cysteine residue in the active sites. In the current study we examined a series of biscoumarins 1–10 for their mechanisms of inhibition with the nickel containing active sites of Jack bean and Bacillus pasteurii ureases. All these compounds competitively inhibited Jack bean urease through interaction with the nickel metallocentre, as deduced from Michaelis-Menten kinetics, UV-visible absorbance spectroscopic, and molecular docking simulation studies. Some of the compounds behaved differently in case of Bacillus pasteurii urease. We conducted the enzyme kinetics, UV-visible spectroscopy, and molecular docking results in terms of the known protein structure of the enzyme. We also evaluated possible molecular interpretations for the site of biscoumarins binding and found that phenyl ring is the major active pharmacophore. The excellent in vitro potency and selectivity profile of the several compounds described combined with their nontoxicity against the human cells and plants suggest that these compounds may represent a viable lead series for the treatment of urease associated problems.

Prevalence of Tuberculosis in District Khar Bajaur Agency, Khyber Pakhtunkhwa Pakistan

Mycobacterium tuberculosis (TB) are a slow-growing facultative intracellular parasite. TB is one of the most common infectious diseases of developing countries including Pakistan. TB is commonly diagnosed by microscopic examination of spontaneously expectorated sputum.

Synthesis, molecular modeling and biological evaluation of 5-arylidene-N,N-diethylthiobarbiturates as potential α-glucosidase inhibitors

BACKGROUND Barbituric acid derivatives are a versatile group of compounds which are identified as potential pharmacophores for the treatment of anxiety, epilepsy and other psychiatric disorders. They are also used as anesthetics and have sound effects on the motor and sensory functions. Barbiturates are malonylurea derivatives with a variety of substituents at C-5 position showing resemblance with nitrogen and sulfur containing compounds like thiouracil which exhibited potent anticancer and antiviral activities. Recently, barbituric acid derivatives have also received great interest for applications in nanoscience. OBJECTIVE Synthesis of 5-arylidene-N,N-diethylthiobarbiturates, biological evaluation as potential α-glucosidase inhibitors and molecular modeling. METHODS In the present study, N,N-Diethylthiobarbituric acid derivatives were synthesized by refluxing of N,N-diethylthiobarbituric acid and different aromatic aldehydes in distilled water. In a typical reaction; a mixture of N,N-diethylthiobarbituric acid 0.20 g (1 mmol) and 5-bromo-2- hydroxybenzaldehyde 0.199 g (1 mmol) mixed in 10 mL distilled water and reflux for 30 minutes. After completion of the reaction, the corresponding product 1 was filtered and dried and yield calculated. It was crystallized from ethanol. The structures of synthesized compounds 1-25 were carried out by using 1H, 13C NMR, EI spectroscopy and CHN analysis used for the determination of their structures. The α-glucosidase inhibition assay was performed as given by Chapdelaine et al., with slight modifications and optimization. RESULTS Our newly synthesized compounds showed a varying degree of α-glucosidase inhibition and at least four of them were found as potent inhibitors. Compounds 6, 5, 17, 11 exhibited IC50 values (Mean±SEM) of 0.0006 ± 0.0002, 18.91 ± 0.005, 19.18 ± 0.002, 36.91 ± 0.003 µM, respectively, as compared to standard acarbose (IC50, 38.25 ± 0.12 µM). CONCLUSION Our present study has shown that compounds 6, 5, 17, 11 exhibited IC50 values of 0.0006 ± 0.0002, 18.91 ± 0.005, 19.18 ± 0.002, 36.91 ± 0.003 µM, respectively. The studies were supported by in silico data analysis.

Therapeutic Potential of Selenium Treated Stem Cells for the Reduction of Liver Fibrosis

Mesenchymal Stem Cells (MSCs) therapy is an alternative way to treat liver fibrosis. The aim of the current study is to enhance the therapeutic potential of MSCs by pretreated with selenium for the reduction of CCl4 induced liver injury. Male Balb/C mice were treated with CCl4 (1.0 μL/g) intraperitoneally, twice a week for 4 weeks. Mouse MSCs were cultured and then pretreated with 15 ng/ml selenium for 24 hrs. The untreated and selenium pretreated MSCs were transplanted into CCl4 injured mice. After two weeks of MSCs transplantation, mice were observed for liver regeneration. The morphological result showed that selenium treated MSCs have significant therapeutic effect in reduction of CCl4 induced injured as compared to untreated MSCs. Biochemical and histopathological result also revealed significant reduction in serum ALT and bilirubin level, collagen content in selenium treated MSCs group as compared to untreated MSCs. Reverse transcriptase PCR result at mRNA level also confirm the antifibrotic effect of selenium treated MSCs on liver fibrosis as evidenced by decreasing the expression level of apoptotic marker and enhancing hepatocyte marker. Thus it is concluded that selenium treated MSCs have a strong therapeutic effect on the reduction of liver fibrosis in CCl4 mice model.

Prevalence of Iron Deficiency Anemia in Pregnant Women of District Mardan, Pakistan

Background: Iron depletion is the most common nutrient deficiency worldwide and is the leading cause of anemia. Anaemia in pregnancy is a common clinical problem contributing to increased maternal and foetal morbidity. Previously few studies have highlighted this problem in developing country like Pakistan but the situation needs further exploration in pregnant women of less developed areas. The current study aimed to estimate the prevalence of iron deficiency anemia (IDA) among pregnant women of district Mardan, Khyber Pakhtunkhwa (KP), Pakistan. Methods: The study consisted of 300 pregnant women in the age group (18-40) years. Blood samples were collected from each pregnant woman and a questionnaire was completed at the time of blood collection. Hematological and biochemical profiles were determined and the collected data was analyzed using SPSS. Results: In the current study the overall prevalence rate of iron deficiency anemia in pregnant women was (76.7%). Iron deficiency anemia was most prevalent in the second trimester (45.7%) as compared to first (16.1%) and third (38.2%) trimester pregnancy. Of the anemic cases, 42.6% have low iron stores and 43.5% have serum ferritin in a range of 12-30 ng/ml. In 60% of cases CRP was raised and 72.2% were multiparous. Of the study population, 65% were uneducated and 87% belonged to lower middle class. Conclusion: This study concluded that anemia is highly prevalent among the antenatal women of this area and iron deficiency considered to the culprit behind this disease. Multiparty, low socio-economic status and low education are the contributory factors of iron deficiency anemia. There is a great need for further health education promotional programs to improve heath of pregnant women.

Design of New and Potent Diethyl Thiobarbiturates as Urease Inhibitors: A Computational Approach

Urease is an important enzyme both in agriculture and medicine research. Strategies based on urease inhibition is critically considered as the first line treatment of infections caused by urease producing bacteria. Since, urease possess agro-chemical and medicinal importance, thus, it is necessary to search for the novel compounds capable of inhibiting this enzyme. Several computational methods were employed to design novel and potent urease inhibitors in this work. First docking simulations of known compounds consists of a set of arylidine barbiturates (termed as reference) were performed on the Bacillus pasteurii (BP) urease. Subsequently, two fold strategies were used to design new compounds against urease. Stage 1 comprised of the energy minimization of enzyme-ligand complexes of reference compounds and the accurate prediction of the molecular mechanics generalized born (MMGB) interaction energies. In the second stage, new urease inhibitors were then designed by the substitution of different groups consecutively in the aryl ring of the thiobarbiturates and N, N-diethyl thiobarbiturates of the reference ligands.. The enzyme-ligand complexes with lowest interaction energies or energies close to the calculated interaction energies of the reference molecules, were selected for the consequent chemical manipulation. This was followed by the substitution of different groups on the 2 and 5 positions of the aryl ring. As a result, several new and potent diethyl thiobarbiturates were predicted as urease inhibitors. This approach reflects a logical progression for early stage drug discovery that can be exploited to successfully identify potential drug candidates.