Yogita Bansal

The therapeutic journey of benzimidazoles: A review

Presence of benzimidazole nucleus in numerous categories of therapeutic agents such as antimicrobials, antivirals, antiparasites, anticancer, anti-inflammatory, antioxidants, proton pump inhibitors, antihypertensives, anticoagulants, immunomodulators, hormone modulators, CNS stimulants as well as depressants, lipid level modulators, antidiabetics, etc. has made it an indispensable anchor for development of new therapeutic agents. Varied substitutents around the benzimidazole nucleus have provided a wide spectrum of biological activities. Importance of this nucleus in some activities like, Angiotensin I (AT(1)) receptor antagonism and proton-pump inhibition is reviewed separately in literature. Even some very short reviews on biological importance of this nucleus are also known in literature. However, owing to fast development of new drugs possessing benzimidazole nucleus many research reports are generated in short span of time. So, there is a need to couple the latest information with the earlier information to understand the current status of benzimidazole nucleus in medicinal chemistry research. In the present review, various derivatives of benzimidazole with different pharmacological activities are described on the basis of substitution pattern around the nucleus with an aim to help medicinal chemists for developing an SAR on benzimidazole derived compounds for each activity. This discussion will further help in the development of novel benzimidazole compounds.

Coumarin hybrids as novel therapeutic agents

Naturally occurring coumarins, having wide spectrum of activities such as antioxidant, anti-inflammatory, anticancer, MAO-B inhibitory and antimicrobial, are frequently used by the researchers to develop novel synthetic and semisynthetic coumarin based therapeutic agents. Many of these agents are hybrid molecules, which are designed through concept of molecular hybridization and have shown multiple pharmacological activities. This multifunctional attribute of these hybrid compounds makes them potential drug candidates for the treatment of multifactorial diseases such as cancer, Alzheimers disease, metabolic syndromes, AIDS, malaria, and cardiovascular diseases. The present review compiles research reports on development of different coumarin hybrids, classify these on the basis of their therapeutic uses and propose structure-activity relationships. It is intended to help medicinal chemist in designing and synthesizing novel and potent hybrid compounds for the treatment of different disorders.

Coumarin: a potential nucleus for anti-inflammatory molecules

Numerous research reports have indicated the coumarin nucleus as a potential candidate for development of anti-inflammatory drugs. Various phytoconstituents such as umbelliferone, scopoletin, columbiatnetin, visniadin, marmin, and many more derived from coumarin nucleus are found to have potent anti-inflammatory as well as antioxidant activities. A large number of coumarin derivatives have also been designed, synthesized, and evaluated to have mild-to-very potent anti-inflammatory activity through different mechanisms. However, despite the continuing efforts in search of these drugs, no major breakthrough has been achieved so far. In the present review, a critical analysis of various reports on naturally as well as the synthetically derived coumarin derivatives having anti-inflammatory activity has been carried out and a structural–activity relationship around the coumarin nucleus has been proposed to assist the medicinal chemists in rationally designing the anti-inflammatory drugs.

Multifunctional compounds: Smart molecules for multifactorial diseases

Multifunctional compounds (MFCs) are designed broadly as hybrid or conjugated drugs or as chimeric drugs from two or more pharmacophores/drugs having specific pharmacological activities. These are capable of eliciting multiple pharmacological actions and have emerged as magic bullets in treatment of multifactorial diseases. Many research articles disclosing the development of such compounds for treatment of multifactorial diseases are published during last 7 years. Some successful MFC candidates for multifactorial CNS disorders include ziprasidone, duloxetine, ladostigil and M-30 whereas sunitinib, lapatinib and synthetic oleandane triterpinoids are the successful MFC candidates for various cancers. Many more compounds derived from berberine, tacrine, artemisnin, quinine, NSAIDs, pralidoxine, donepezil, rivastigmine, curcumin and various antioxidants are under investigations for exploration of their multifunctional potential. In general, MFCs possess the advantages of reduced molecularity, no drug-drug interactions and improved pharmacokinetics and pharmacodynamics. A MFC derived from two or more different pharmacophores exerts its activities by interacting with respective receptors of its constituent pharmacophores. It may also exhibit additional binding interactions with the receptor sites that may be responsible for significantly improved or additional activities. The present review discusses various MFCs developed for specific class of disorders with an aim to provide an insight into the strategies in medicinal chemistry for development of such compounds.

Novel coumarin-benzimidazole derivatives as antioxidants and safer anti-inflammatory agents.

Inspired from occurrence of anti-inflammatory activity of 3-substituted coumarins and antiulcer activity of various 2-substituted benzimidazoles, novel compounds have been designed by coupling coumarin derivatives at 3-position directly or through amide linkage with benzimidazole nucleus at 2-position. The resultant compounds are expected to exhibit both anti-inflammatory and antioxidant activities along with less gastric toxicity profile. Two series of coumarin–benzimidazole derivatives (4a–e and 5a–e) were synthesized and evaluated for anti-inflammatory activity and antioxidant activity. Compounds 4c, 4d and 5a displayed good anti-inflammatory (45.45%, 46.75% and 42.85% inhibition, respectively, versus 54.54% inhibition by indomethacin) and antioxidant (IC50 of 19.7, 13.9 and 1.2 µmol/L, respectively, versus 23.4 µmol/L for butylatedhydroxytoluene) activities. Evaluation of ulcer index and in vivo biochemical estimations for oxidative stress revealed that compounds 4d and 5a remain safe on gastric mucosa and did not induce oxidative stress in tissues. Calculation of various molecular properties suggests the compounds to be sufficiently bioavailable.

Design, synthesis, and evaluation of 5-sulfamoyl benzimidazole derivatives as novel angiotensin II receptor antagonists

A series of 5-alkylsulfamoyl benzimidazole derivatives have been designed and synthesized as novel angiotensin II (Ang II) receptor antagonists. The compounds have been evaluated for in vitro Ang II antagonism and for in vivo antihypertensive activity on isolated rat aortic ring and desoxycortisone acetate induced hypertensive rats, respectively. The activity is found related to size of alkyl group. The maximum activity is observed with a compact and bulky alkyl group like tert-butyl and cyclohexyl. The compounds 4g and 4h have shown promising both in vitro and in vivo activities. A receptor binding model is also proposed on the basis on the basis of structure-activity relationship in this study.

Anti-inflammatory and antinociceptive activity of vanillin

Objective: Vanillin is known to have antimutagenic, anti-invasive, and metastatic suppression potential. Antinociceptive property in acetic acid and antioxidant and hepatoprotective properties in carbon tetrachloridetreated rats have also been demonstrated. Objective of this study is to evaluate the anti-inflammatory and antinociceptive activity of vanillin. Materials and Methods: The drugs and fine chemicals were purchased from Sigma Aldrich, Ranbaxy, India and MS Pharmaceuticals, India. Experimental Rats were assigned to groups of six animals each and anti-inflammatory activity was evaluated using carrageenan induced rat paw aedema and anti-nocicetion was done using tail flick method. Carrageenan-induced paw edema was used to evaluate pre and post anti-inflammatory activity and tail flick method was used in the evaluation of antinociceptive activity. Two-way analysis of variance (ANOVA) followed by Students t-test was used for statistical analysis in both the studies. Results: There was significant decrease in the paw volume at 50 and 100 mg/kg doses of vanillin when compared with control group. Meanwhile, an increase in percentage maximum possible effect (MPE) was seen by same doses of vanillin. Conclusion: It has been concluded from the findings that vanillin possesses the anti-inflammatory and antinociceptive effect by virtue of its antihistaminic and central analgesic activity, respectively.

Accelerated Stability Studies on Dried Extracts of Centella asiatica Through Chemical, HPLC, HPTLC, and Biological Activity Analyses

Regulatory guidelines recommend systematic stability studies on a herbal product to establish its shelf life. In the present study, commercial extracts (Types I and II) and freshly prepared extract (Type III) of Centella asiatica were subjected to accelerated stability testing for 6 months. Control and stability samples were evaluated for organoleptics, pH, moisture, total phenolic content (TPC), asiatic acid, kaempherol, and high-performance thin layer chromatography fingerprints, and for antioxidant and acetylcholinesterase inhibitory activities. Markers and TPC and both the activities of each extract decreased in stability samples with respect to control. These losses were maximum in Type I extract and minimum in Type III extract. Higher stability of Type III extract than others might be attributed to the additional phytoconstituents and/or preservatives in it. Pearson correlation analysis of the results suggested that TPC, asiatic acid, and kaempferol can be taken as chemical markers to assess chemical and therapeutic shelf lives of herbal products containing Centella asiatica.

Synthesis and PASS-assisted evaluation of coumarin–benzimidazole derivatives as potential anti-inflammatory and anthelmintic agents

Two series of novel derivatives have been designed by coupling medicinally important coumarin and benzimidazole nuclei through different linkers. These compounds have been predicted to be potent anti-inflammatory and anthelmintic by in silico studies using PASS (prediction of activity spectra for substances) software. The compounds are synthesized and evaluated for the predicted activities as well as for their in vitro antioxidant potential. Compounds of first series (4a–4f) are found good to moderate anti-inflammatory agents. Among these, compounds 4b and 4f exhibited maximum anti-inflammatory activity (45% inhibition), which is equivalent to the activity of indomethacin (48% inhibition) after 3 h (peak inflammatory response time). Compounds of second series (5a–5f) exhibit anthelmintic activity. Amongst these, compound 5f has mortality activity marginally higher than albendazole (10–11 s). Compound 5e is found to be the most potent antioxidant with remarkable EC50 value (0.08 µM/mL), which is though a little less than that of ascorbic acid (0.03 µM/mL). In addition, a comparative analysis of calculated Lipinski’s parameters reveals that all test compounds have the propensity to be orally bioavailable. Based on these findings, compounds 4b, 4f, 5e, and 5f are identified as new leads to develop potent anti-inflammatory, anthelmintic, and antioxidant compounds.

Understanding unconventional routes to impurities from drugs in hydrolytic conditions

Introduction: Hydrolytic degradation is the most common cause of formation of impurities or degradation products in drugs during different stages of drug product development and/or shelf life of the drug/product. Degradation products formed by hydrolysis of ester, amide, urethane, sulfonamide, sulfonate and ether linkages, and of nitrile, hydroxyl and amino groups in drugs can be conveniently predicted and identified. Many drugs are known to degrade to such expected conventional hydrolytic degradation products, and the mechanisms of such degradations are also well known and reported. However, many drugs are reported to degrade under hydrolytic conditions to products, which cannot be justified by the conventional hydrolytic reactions. Objectives: Though structures of such unconventional hydrolytic products can be characterized through different spectral techniques, but there is a need to understand the mechanisms of such unconventional hydrolytic reactions in order to help in establishing intrinsic stability characteristics of a drug. Methodology: In the present review, we have studied and critically analysed all possible reports on hydrolytic degradation of various dugs to provide a thorough insight into unconventional routes of hydrolytic degradations of drugs. The various unconventional hydrolytic reactions found responsible for degradation of drugs are classified as oxidation, dehydrogenation, coupling/condensation, N-alkylation, C-C bond cleavage, C-N bond cleavage, dehalogenation, cyclization, decarboxylation and hydroxylation. Discussion: Varied types of reactions under hydrolytic conditions are triggered/controlled by the nature of substituent(s) across or around the susceptible bonds/groups. The mechanisms for such unconventional hydrolytic reactions have been discussed or proposed with support from the standard literature. The contents are expected to enable an analyst and a drug formulator to predict various possible as well as seemingly improbable hydrolytic degradation products of a drug well ahead of systematic forced degradation studies.