Applications of Metformin in Dentistry-A review.

Metformin is a versatile drug with numerous medical uses. It is known primarily as an anti-hyperglycemic drug that has become the main oral blood-glucose-lowering medication for managing type 2 diabetes mellitus globally. Its use has been reported in a variety of oral conditions and dentistry in general. Recent clinical trials have indicated the effectiveness of adjunct topical application of metformin in improving the periodontal parameters of patients with diabetes and periodontitis. Additionally, studies have suggested that metformin stimulates odontogenic differentiation and mineral synthesis of stem cells in the tooth pulp. Metformin also stimulates osteoblast proliferation, decreases osteoclast activity and exerts regenerative effects on periodontal bone, thus making it a viable candidate for periodontal regeneration. Metformin monotherapy significantly enhances osseointegration of endosseous implants and has been reported to have anti-cancer effects on oral squamous cell carcinoma by impeding tumor progression. Animal studies have indicated that metformin improves orthodontic tooth movement and resists orthodontic appliance corrosion. This narrative review aims to provide a current summary of research highlighting the prospective uses of metformin in dentistry.

Synthesis, ß-glucuronidase inhibition and molecular docking studies of cyano-substituted bisindole hydrazone hybrids.

The ß-glucuronidase, a lysosomal enzyme, catalyzes the cleavage of glucuronosyl-O-bonds. Its inhibitors play a significant role in different medicinal therapies as they cause a decrease in carcinogen-induced colonic tumors by reducing the level of toxic substances present in the intestine. Among those inhibitors, bisindole derivatives had displayed promising ß-glucuronidase inhibition activity. In the current study, hydrazone derivatives of bisindolymethane (1-30) were synthesized and evaluated for in vitro ß-glucuronidase inhibitory activity. Twenty-eight analogs demonstrated better activity (IC50 = 0.50-46.5 µM) than standard D-saccharic acid 1,4-lactone (IC50 = 48.4 ± 1.25 µM). Compounds with hydroxyl group like 6 (0.60 ± 0.01 µM), 20 (1.50 ± 0.10 µM) and 25 (0.50 ± 0.01 µM) exhibited the most potent inhibitory activity, followed by analogs with fluorine 21 (3.50 ± 0.10 µM) and chlorine 23 (8.20 ± 0.20 µM) substituents. The presence of hydroxyl group at the aromatic side chain was observed as the main contributing factor in the inhibitory potential. From the docking studies, it was predicted that the active compounds can fit properly in the binding groove of the ß-glucuronidase and displayed significant binding interactions with essential residues.

Synthesis and molecular modelling studies of phenyl linked oxadiazole-phenylhydrazone hybrids as potent antileishmanial agents.

Molecular hybridization yielded phenyl linked oxadiazole-benzohydrazones hybrids 6-35 and were evaluated for their antileishmanial potentials. Compound 10, a 3,4-dihydroxy analog with IC50 value of 0.95 ± 0.01 µM, was found to be the most potent antileishmanial agent (7 times more active) than the standard drug pentamidine (IC50 = 7.02 ± 0.09 µM). The current series 6-35 conceded in the identification of thirteen (13) potent antileishmanial compounds with the IC50 values ranging between 0.95 ± 0.01-78.6 ± 1.78 µM. Molecular docking analysis against pteridine reductase (PTR1) were also performed to probe the mode of action. Selectivity index showed that compounds with higher number of hydroxyl groups have low selectivity index. Theoretical stereochemical assignment was also done for certain derivatives by using density functional calculations.

Synthesis of 6-chloro-2-Aryl-1H-imidazo[4,5-b]pyridine derivatives: Antidiabetic, antioxidant, ß-glucuronidase inhibiton and their molecular docking studies.

6-Chloro-2-Aryl-1H-imidazo[4,5-b]pyridine derivatives 1-26 were synthesized and characterized by various spectroscopic techniques. All these derivatives were evaluated for their antiglycation, antioxidant and ß-glucuronidase potential followed their docking studies. In antiglycation assay, compound 2 (IC50=240.10±2.50µM) and 4 (IC50=240.30±2.90µM) was found to be most active compound of this series, while compounds 3 (IC50=260.10±2.50µM), 6 (IC50=290.60±3.60µM), 13 (IC50=288.20±3.00µM) and 26 (IC50=292.10±3.20µM) also showed better activities than the standard rutin (IC50=294.50±1.50µM). In antioxidant assay, compound 1 (IC50=69.45±0.25µM), 2 (IC50=58.10±2.50µM), 3 (IC50=74.25±1.10µM), and 4 (IC50=72.50±3.30µM) showed good activities. In ß-glucuronidase activity, compounds 3 (IC50=29.25±0.50µM), compound 1 (IC50=30.10±0.60µM) and compound 4 (IC50=46.10±1.10µM) showed a significant activity as compared to than standard D-Saccharic acid 1,4-lactonec (IC50=48.50±1.25µM) and their interaction with the enzyme was confirm by docking studies.

Synthesis, In vitro and Docking Studies of New Flavone Ethers as α-Glucosidase Inhibitors.

We report herein the synthesis, α-glucosidase inhibition and docking studies for a series of 3-15 new flavones. A simple nucleophilic substitution reaction takes place between 3'hydroxyflavone (2) with halides to afford the new flavones. Chalcone (1), 3'hydroxyflavone (2) and the newly synthesized flavones (3-15) were being evaluated for their ability to inhibit activity of α-glucosidase. Compounds 2, 3, 5, 7-10 and 13 showed good inhibitory activity with IC50 values ranging between 1.26 and 36.44 µM as compared to acarbose (IC50 = 38.25 ± 0.12 µM). Compounds 5 (5.45 ± 0.08 µM), 7 (1.26 ± 0.01 µM) and 8 (8.66 ± 0.08 µM) showed excellent inhibitory activity, and this may be due to trifluoromethyl substitution that is common for these compounds. Compound 7, a 2,5-trifluoromethyl-substituted compound, recorded the highest inhibition activity, and it is thirty times better than the standard drug. Docking studies for compound 7 suggest that both trifluoromethyl substituents are well positioned in a binding pocket surrounded by Phe300, Phe177, Phe157, Ala278, Asp68, Tyr71 and Asp214. The ability of compound 7 to interact with Tyr71 and Phe177 is extremely significant as they are found to be important for substrates recognition by α-glucosidase.

Synthesis of novel flavone hydrazones: in-vitro evaluation of α-glucosidase inhibition, QSAR analysis and docking studies.

Thirty derivatives of flavone hydrazone (5-34) had been synthesized through a five-step reaction and screened for their α-glucosidase inhibition activity. Chalcone 1 was synthesized through aldol condensation then subjected through oxidative cyclization, esterification, and condensation reaction to afford the final products. The result for baker's yeast α-glucosidase (EC 3.2.1.20) inhibition assay showed that all compounds are active with reference to the IC50 value of the acarbose (standard drug) except for compound 3. Increase in activity observed for compounds 2 to 34 clearly highlights the importance of flavone, hydrazide and hydrazone linkage in suppressing the activity of α-glucosidase. Additional functional group on N-benzylidene moiety further enhances the activity significantly. Compound 5 (15.4 ± 0.22 µM), a 2,4,6-trihydroxy substituted compound, is the most active compound in the series. Other compounds which were found to be active are those having chlorine, fluorine, and nitro substituents. Compounds with methoxy, pyridine, and methyl substituents are weakly active. Further studies showed that they are not active in inhibiting histone deacetylase activity and do not possess any cytotoxic properties. QSAR model was being developed to further identify the structural requirements contributing to the activity. Using Discovery Studio (DS) 2.5, various 2D descriptors were being used to develop the model. The QSAR model is able to predict the pIC50 and could be used as a prediction tool for compounds having the same skeletal framework. Molecular docking was done for all compounds using homology model of α-glucosidase to identify important binding modes responsible for inhibition activity.

Synthesis of novel derivatives of 4-methylbenzimidazole and evaluation of their biological activities.

4-Methylbenzimidazole 1-28 novel derivatives were synthesized and evaluated for their antiglycation and antioxidant activities. Compounds 1-7 and 11 showed excellent activities ranged 140-280 µM, better than standard drug rutin (294.46 ± 1.50 µM). Compound 1-28 were also evaluated for DPPH activities. Compounds 1-8 showed excellent activities, ranging 12-29 µM, better than standard drug n-propylgallate (IC50 = 30.30 ± 0.40 µM). For superoxide anion scavenging activity, compounds 1-7 showed better activity than standard n-propylgallate (IC50 = 106.34 ± 1.6 µM), ranged 82-104 µM. These compounds were found to be nontoxic to THP-1 cells.

Synthesis, crystal structure, DFT studies and evaluation of the antioxidant activity of 3,4-dimethoxybenzenamine schiff bases.

Schiff bases of 3,4-dimethoxybenzenamine 1-25 were synthesized and evaluated for their antioxidant activity. All the synthesized compounds were characterized by various spectroscopic techniques. In addition, the characterizations of compounds 13, 15 and 16 were supported by crystal X-ray determinations and their geometrical parameters were compared with theoretical DFT calculations at the B3LYP level of theory. Furthermore, the X-ray crystal data of two non-crystalline compounds 8 and 18 were theoretically calculated and compared with the practical values of compounds 13, 15, 16 and found a good agreement. The compounds showed good DPPH scavenging activity ranging from 10.12 to 84.34 µM where compounds 1-4 and 6 showed stronger activity than the standard n-propyl gallate. For the superoxide anion radical assay, compounds 1-3 showed better activity than the standard.

Synthesis, evaluation of antioxidant activity and crystal structure of 2,4-dimethylbenzoylhydrazones.

2,4-Dimethylbenzoylhydrazones 1-30 were synthesized by condensation reactions of 2,4-dimethylbenzoylhydrazide with various aromatic aldehydes and characterized. The assigned structures of compounds 10, 15 and 22 were further supported by single-crystal X-ray diffraction data. The synthesized compounds were evaluated for their in vitro DPPH radical scavenging activity. They exerted varying degree of scavenging activity toward DPPH radical with IC50 values between 25.6-190 µM. Compounds 1, 4, 2, 3, 7, and 6 have IC50 values of 25.6, 28.1, 29.3, 29.8, 30.0 and 30.1 µM respectively, showing better activity than an n-propyl gallate standard (IC50 value = 30.30 µM). For super oxide anion scavenging activity compounds 1, 2 and 3 with IC50 values of 98.3, 102.6, and 105.6, respectively, also showed better activity than the n-propyl gallate standard (IC50 value = 106.34 µM).

Vitamin D deficiency in fibromyalgia.

OBJECTIVE: To check the Vitamin D levels in patients diagnosed as fibromyagia in our population. METHODS: Study was done at Medical OPD of Civil Hospital Karachi, from January to March 2009. Female patients diagnosed as Fibromyalgia according to American College of Rheumatology (ACR) criteria and exclusion of systemic illness on examination, and normal reports of blood CP, ESR, serum calcium, phosphate and Alkaline Phosphatase, were asked to get Vitamin D levels in their serum. Vitamin D deficiency is defined as <20 ng/ml, Vitamin D insufficiency 21-29 ng/ml and Vitamin D sufficiency equal or >30 ng/ml. RESULT: Forty female patients were included in the study. The mean age was 37.65 +/- 11.5 years. Mean Vitamin D level was 17.41 +/- 5.497 ng/ml. Thirty two (80%) of patients had Vitamin D deficiency, mean levels of 15.855 +/- 4.918 ng/ml and 8(20%) had Vitamin D insufficiency, mean levels of 23.64 +/- 2.39 ng/ml. Patients with vitamin D deficiency and age less than 45 years were 22 (68.75%), had mean vitamin D level 16.87 +/- 4.48 ng/ml whereas in age ranging from 46-75 years were 10 (31.25%) had mean vitamin D level 16.09 +/- 6.45 ng/ml. CONCLUSION: Vitamin D deficiency is frequently seen in patients diagnosed as fibromyalgia and nonspecific musculoskeletal pain in our population. Although the sample size of the study is small, but the figures are so alarming that it is an eye opener towards the need of a population based study, including normal population as well as those presenting with musculoskeletal pain.