Synthesis, QSAR study and Pharmacological Evaluation of Novel Triazolidine-2-thione Analogues as Antimicrobial, Anti-inflammatory and Antioxidant agents.

BACKGROUND: The triazole analogues are molecules of immense attraction because of their wide pharmacological applications. METHODS: Present research deals with the synthesis of triazole-2-thione analogues and their QSAR study. The synthesized analogs are also evaluated for their antimicrobial, anti-inflammatory, and antioxidant effect. RESULTS: It was revealed that the benzamide analogues (3a, 3d) and triazolidine analogue (4b) were found to be most active against P. aeruginosa and E. coli with pMIC values of 1.69, 1.69 and 1.72, respectively. The antioxidant study of the derivatives showed that 4b was the most active antioxidant with 79% protein denaturation inhibition. The highest anti-inflammatory activity was shown by 3f, 4a and 4f. CONCLUSION: This study provides certain potent leads for further development of more potential anti-inflammatory, antioxidant and antimicrobial agents.

Advances in Synthesis, Derivatization and Bioactivity of Isatin: A Review.

BACKGROUND: Isatin (IST) is a crucial pharmacologically active compound, chemically known as indole- 1H-2,3-dione. Development of different IST based analogues acquired significant awareness because of its pronounced therapeutic importance such as analgesic, anticancer, anti-inflammatory, antitubercular, antimicrobial, antifungal, antiviral (effective against SARS coronavirus 3C protease) and many other activities, and represents an important class of heterocyclic compounds that can be used as a precursor for the synthesis of many useful drugs. OBJECTIVE: Previously, many articles were reported on IST synthesis and its different pharmacological activities but herein, we mentioned 59 different synthesis schemes of several IST derivatives/hybrids derived from the substitution of the nitrogen, aromatic ring, the second and third position of IST along with most potent molecule among each of synthesized libraries with their structural activity relationship (SAR). Using these standardized approaches, several biologically important compounds were developed like sunitinib, nintedanib, indirubin, etc and several studies have been carried out nowadays to develop newer compounds having fewer side effects and also overcome the problem of resistance. CONCLUSION: This report critically reviews the different strategies for the designs and synthesis of several IST based compounds having different biological activities with SAR, which can favour further investigation and modification for the development of new and more potent entities.

Enantioselective Box Behenken Optimized HPLC-DAD Method for the Simultaneous Estimation of Alogliptin Enantiomorphs in Pharmaceutical Formulations and their Pharmacokinetic Study in Rat Plasma.

Purpose: A stereoselective high performance liquid chromatographic analytical method with photodiode array detector was developed and validated as per the International Conference on Harmonization (ICH) guidelines for the determination of alogliptin (ALO) enantiomers in formulations and rat plasma. Methods: Enantiomeric separation was performed on a Phenomenex Lux Cellulose-2 chiral column. Box-Behnken design was used to identify the optimum conditions of the three independent variables for the desired output responses. Results: The HPLC peaks of ALO enantiomers and the internal standard pioglitazone were achieved before 8 min with a resolution of 0.77 min between R and S enantiomer and resolution of more than 2.0 between each enantiomer and pioglitazone (internal) with more than 95% recovery. The linearity range and the limit of quantification of both the enantiomers in rat plasma were 10-70 ng mL-1 and 1.2 ng mL-1 respectively. Conclusion: The developed method after validation was successfully applied for estimation of ALO enantiomers in formulations. Single oral dose of 25 mg of the ALO racemate tablets were administered to a group of 6 healthy rats for a comparative pharmacokinetic study of both the enantiomers.

Novel hybrids of benzothiazole-1,3,4-oxadiazole-4-thiazolidinone: Synthesis, in silico ADME study, molecular docking and in vivo anti-diabetic assessment.

A series of new benzothiazole-1,3,4-oxadiazole-4-thiazolidinone hybrid analogs (Tz1-Tz28) were synthesized in search of potential anti-diabetic agents. Molecular docking study was conducted with binding pocket of peroxisome proliferator activated receptor-gamma to elucidate the binding interactions of newly synthesized targets. Seven selected compounds with best docking scores were further screened for in vivo anti-hyperglycemic efficacy by oral glucose tolerance test in non-diabetic rats and on streptozotocin induced diabetic rat models. All the tested compounds demonstrated excellent to moderate reduction in blood glucose levels. Three of the compounds (Tz21, Tz7 and Tz10) showed excellent anti-diabetic effect by reducing concentration of glucose to 157.15 ±â€¯1.79 mg/dL, 154.39 ±â€¯1.71 mg/dL, 167.36 ±â€¯2.45 mg/dL, respectively better than the standard drug, pioglitazone, 178.32 ±â€¯1.88 mg/dL. Moreover, three derivatives Tz21, Tz4 and Tz24 with IC50 values of 0.21 ±â€¯0.01 µM, 9.03 ±â€¯0.12 µM and 11.96 ±â€¯0.40 µM respectively also showed better inhibitory activities on alpha-glucosidase even more than the standard acarbose (IC50 = 18.5 ±â€¯0.20 µM), indicating Tz21 has the highest inhibitory effect among the seven tested derivatives. Prediction of Drug like properties using molinspiration online software suggests that all the synthesized compounds have potential of becoming the orally active molecules. Thus, these novel hybrids could serve as potential candidates to become leads for the development of new drugs eliciting anti-hyperglycemic effect orally.

Synthesis, ADME, docking studies and in vivo anti-hyperglycaemic potential estimation of novel Schiff base derivatives from octadec-9-enoic acid.

A new series of octadec-9-enoic acid schiff base entities (S1-S30) were designed and synthesized targeting peroxisome proliferator activated receptor-gamma for agonist action. Molinspiration software (online) was used to estimate drug like molecular properties of the metabolites. Docking disquisition on co-crystallized protein of PPAR-γ (PDB ID 1FM9) was carried out which showed S21, S10 and S7 as best situated in the vital sites of receptor having docking scores -9.19, -8.68 and -8.64 respectively. Free binding energy measured using model of Maestro 9.0 and was in range of from -40.01 and -80.54 kcal/mol, significant when compared with pioglitazone (-51.58 Kcal/mol). Seven best docked derivatives were assessed for in-vivo oral glucose tolerance on normal rats and anti-hyperglycaemic activity by streptozotocin induced diabetes model. S21 unveiled to be the best measured analogue among all the synthesized entities. Encouraging outcomes motivates fatty acids for further development of more effective and safer compounds.

Synthesis, molecular modelling studies and ADME prediction of benzothiazole clubbed oxadiazole-Mannich bases, and evaluation of their anti-diabetic activity through in vivo model.

A small library of new benzothiazole clubbed oxadiazole-Mannich bases (M-1 to M-22) were synthesized and characterized by IR, NMR, Mass and Elemental analysis results. Molecular docking studies were done to assess the binding mode and interactions of synthesized hits at binding site of receptor Peroxisome proliferator-activated receptor, PPAR-γ or PPARG (PDB 1FM9). Among the synthesized compounds, nine compounds were selected on the basis of docking score and evaluated for their in vivo anti-diabetic activity using Oral Glucose Tolerance Test (OGTT) in normal rats followed by Streptozotocin (STZ) - induced diabetes. Results indicated that compound M-14 (161.39 ±â€¯4.38) showed the highest reduction of blood glucose level comparable to that of the standard drug glibenclamide (140.29 ±â€¯1.24) in STZ model. Other compounds exhibited moderate to good anti hyperglycaemic activity. ADME studies was done using Molinspiration online software, revealed that all compounds (except M-11) are likely to be orally active as they obeyed Lipinski's rule of five.

Synthesis, molecular properties, toxicity and biological evaluation of some new substituted imidazolidine derivatives in search of potent anti-inflammatory agents.

The aim of this study was to design and synthesize pharmaceutical agents containing imidazolidine heterocyclic ring in the hope of developing potent, safe and orally active anti-inflammatory agents. A number of substituted-imidazolidine derivatives (3a-k) were synthesized starting from ethylene diamine and aromatic aldehydes. The imidazolidine derivatives (3a-k) were investigated for their anticipated anti-inflammatory, and analgesic activity in Wistar albino rats and Swiss albino mice, respectively. Bioactivity score, molecular and pharmacokinetic properties of the imidazolidine derivatives were calculated by online computer software programs viz. Molinspiration and Osiris property explorer. The results of biological testing indicated that among the synthesized compounds only three imidazolidine derivatives namely 4-[1,3-Bis(2,6-dichlorobenzyl)-2-imidazolidinyl]phenyl-diethylamine (3g), 4-[1,3-Bis(3-hydroxy-4-methoxybenzyl)-2-imidazolidinyl]phenyl-diethylamine (3i) and 4-(1,3-Bis(4-methoxybenzyl)-4-methylimidazolidin-2-yl)-phenyl-diethylamine (3j) possess promising anti-inflammatory and analgesic actions. Additionally these derivatives displayed superior GI safety profile (low severity index) with respect to the positive control, Indomethacin. All synthesized compounds showed promising bioactivity score for drug targets by Molinspiration software. Almost all the compounds were predicted to have very low toxicity risk by Osiris online software. Compound number (3i) emerged as a potential candidate for further research as it obeyed Lipinski's rule of five for drug likeness, exhibited promising biological activity in-vivo and showed no risk of toxicity in computer aided screening.