Om Silakari

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.

Flavones: An important scaffold for medicinal chemistry

Flavones have antioxidant, anti-proliferative, anti-tumor, anti-microbial, estrogenic, acetyl cholinesterase, anti-inflammatory activities and are also used in cancer, cardiovascular disease, neurodegenerative disorders, etc. Also, flavonoids are found to have an effect on several mammalian enzymes like protein kinases that regulate multiple cell signaling pathways and alterations in multiple cellular signaling pathways are frequently found in many diseases. Flavones have been an indispensable anchor for the development of new therapeutic agents. The majority of metabolic diseases are speculated to originate from oxidative stress, and it is therefore significant that recent studies have shown the positive effect of flavones on diseases related to oxidative stress. Due to the wide range of biological activities of flavones, their structure-activity relationships have generated interest among medicinal chemists. The outstanding development of flavones derivatives in diverse diseases in very short span of time proves its magnitude for medicinal chemistry research. The present review gives detail about the structural requirement of flavone derivatives for various pharmacological activities. This information may provide an opportunity to scientists of medicinal chemistry discipline to design selective, optimize as well as poly-functional flavone derivatives for the treatment of multi-factorial diseases.

Acetylcholinesterase inhibitors as Alzheimer therapy: from nerve toxins to neuroprotection.

Acetylcholinesterase is a member of the α/β hydrolase protein super family, with a significant role in acetylcholine-mediated neurotransmission. Research in the modulators of AChEs has moved from a potent poison (Sarin, Soman) in war times to the potent medicine (physostigmine) in peaceful times. Natural anti-AChE includes carbamates, glycoalkaloids, anatoxins derived from green algae; synthetic anti-AChE includes highly poisonous organophosphates used as nerve gases and insecticides. Recently, the role of anti-AChE was reassessed from neurotoxins to neuron-protective in the diseases characterized by impaired acetylcholine-mediated neurotransmission like Alzheimers disease (AD). So, the AChE has been proven to be the most viable therapeutic target for the symptomatic treatment of AD. This review article gives a spectrum of strategies to design AChE inhibitors used in the Alzheimer therapy.

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.

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.

Oxindole: A chemical prism carrying plethora of therapeutic benefits.

Oxindole has emerged as a valuable scaffold in medicinal chemistry possessing diverse range of pharmacological activities. Its value has further been increased by its natural occurrence as alkaloids in variety of plants. It was first extracted from the cat claws plant Uncaria tomentosa found in the Amazon rainforest and other tropical areas of South and Central America. Traditionally as well as present emerging therapeutic potential of oxindole nucleus has captured the interest of medicinal chemists to synthesize novel oxindole derivatives. In the present review the authors have integrated its chemistry and synthetic strategies developed after 1945. Also the information of naturally occurring oxindole alkaloids has been incorporated. The detailed pharmacological activities including anti-cancer, anti-HIV, antidiabetic, antibacterial, antioxidant, kinase inhibitory, AChE inhibitory, anti-leishmanial, β3 adrenergic receptor agonistic, phosphatase inhibitory, analgesic, spermicidal, vasopressin antagonists, progesterone antagonists, neuroprotection, and NMDA blocker activities of oxindole derivatives alongwith their SAR has also been discussed in detail. Additionally, information regarding the oxindole derivatives in clinical trials has been incorporated. Thus, this review will provide insights for the synthetic as well as medicinal chemist for the designing and synthesis of novel oxindole derivatives with novel improved range of pharmacological implications.

Indoles as therapeutics of interest in medicinal chemistry: Bird's eye view

Indoles constitute extensively explored heterocyclic ring systems with wide range of applications in pathophysiological conditions that is, cancer, microbial and viral infections, inflammation, depression, migraine, emesis, hypertension, etc. Presence of indole nucleus in amino acid tryptophan makes it prominent in phytoconstituents such as perfumes, neurotransmitters, auxins (plant hormones), indole alkaloids etc. The interesting molecular architecture of indole makes them suitable candidates for the drug development. This review article provides an overview of the chemistry, biology, and toxicology of indoles focusing on their application as drugs. Our effort is to corroborate the information available on the natural indole alkaloids, indole based FDA approved drugs and clinical trial candidates having diverse therapeutic implementations. This compiled information may serve as a benchmark for the alteration of existing ligands to design novel potent molecules with lesser side effects.

Inhibitors of switch kinase ‘spleen tyrosine kinase’ in inflammation and immune-mediated disorders: A review

Spleen tyrosine kinase (Syk), a member of Syk family of non-receptor protein tyrosine kinases plays a significant role in the immune cell signaling in B cells, mast cells, macrophages and neutrophils. Anomalous regulation of this kinase can lead to different allergic disorders and antibody-mediated autoimmune diseases such as rheumatoid arthritis, asthma, psoriasis and allergic rhinitis. Being involved in the growth and survive mechanism of B cells, its inhibition can be beneficial in B-cell lymphoma. Thus, Syk can be sited as a therapeutically relevant target for various allergic and autoimmune disorders. This review article describes the structure of Syk and its role in B-cell signaling. In addition to this, data regarding small molecule inhibitors of Syk has also been reviewed from different papers and patents published.

Hybrids: a new paradigm to treat Alzheimer's disease

Alzheimer‘s disease (AD) is a complex neurodegenerative condition with several target proteins contributing to its etiology. With 35.6 million cases worldwide documented in 2011, AD constitutes a devastating health, political, economic, and social problem for all nations. The cases are expected to increase beyond 107 million in 2050; unless an advanced therapy having a capability to delay the disease progression is developed. The curative paradigm of one-compound one-target that has been followed so far has not reached the desired mark. The research focus moved towards single molecule targeting two or more pathogenic mechanisms involved in neuronal death. Over the last few years, medicinal chemists have been paying attention to the design and synthesis of the hybrid molecules that are comprised of two pharmacophores from well-established chemical scaffolds endowed with requisite biological activities in a single entity. The hybrid-based approach has grown to be a central point in the medicinal chemistry field. Various important pharmacophores used for AD have been combined with selected biologically active molecules to get homo- and heterodimers with improved efficacy with additional supplementary actions. This review summarizes the pathogenesis of AD and various progress in the design of hybrid molecules based on the one-compound-various targets paradigm for AD therapy.

Inhibitors of microsomal prostaglandin E2 synthase-1 enzyme as emerging anti-inflammatory candidates.

Cyclooxygenases (COX‐1 and COX‐2) catalyze the conversion of arachidonic acid (AA) into PGH2 that is further metabolized by terminal prostaglandin (PG) synthases into biologically active PGs, for example, prostaglandin E2 (PGE2), prostacyclin I2 (PGI2), thromboxane A2 (TXA2), prostaglandin D2 (PGD2), and prostaglandin F2 alpha (PGF2α). Among them, PGE2 is a widely distributed PG in the human body, and an important mediator of inflammatory processes. The successful modulation of this PG provides a beneficial strategy for the potential anti‐inflammatory therapy. For instance, nonsteroidal anti‐inflammatory agents (NSAIDs), both classical nonselective (cNSAIDs) and the selective COX‐2 inhibitors (coxibs) attenuate the generation of PGH2 from AA that in turn reduces the synthesis of PGE2 and modifies the inflammatory conditions. However, the long‐term use of these agents causes severe side effects due to the nonselective inhibition of other PGs, such as PGI2 and TXA2, etc. Microsomal prostaglandin E2 synthase‐1 (mPGES‐1), a downstream PG synthase, specifically catalyzes the biosynthesis of COX‐2‐derived PGE2 from PGH2, and describes itself as a valuable therapeutic target for the treatment of acute and chronic inflammatory disease conditions. Therefore, the small molecule inhibitors of mPGES‐1 would serve as a beneficial anti‐inflammatory therapy, with reduced side effects that are usually associated with the nonselective inhibition of PG biosynthesis.