Metal- and Phenol-Free Synthesis of Biaryl Ethers: Access to Dibenzobistriazolo-1,4,7-oxadiazonines and Vancomycin-Like Glyco-Macrocycles as Antibacterial Agents.

An efficient synthesis of biaryl ethers, from electron-deficient aryl halides using NaH/DMSO under metal- and phenol-free conditions, has been achieved to access dibenzo-bistriazolo-1,4,7-oxadiazonines and vancomycin-like glyco-macrocycles. A 44-membered glyco-macrocycle showed promising activity against vancomycin-resistant Staphylococcus aureus (VRSA).

Identification of gallic acid based glycoconjugates as a novel tubulin polymerization inhibitors.

A novel class of gallic acid based glycoconjugates were designed and synthesized as potential anticancer agents. Among all the compounds screened, compound 2a showed potent anticancer activity against breast cancer cells. The latter resulted in tubulin polymerization inhibition and induced G2/M cell cycle arrest, generation of reactive oxygen species, mitochondrial depolarization and subsequent apoptosis in breast cancer cells. In addition, ultraviolet-visible spectroscopy and fluorescence quenching studies of the compound with tubulin confirmed direct interaction of compounds with tubulin. Molecular modeling studies revealed that it binds at the colchicine binding site in tubulin. Further, 2a also exhibited potent in vivo anticancer activity in LA-7 syngeneic rat mammary tumor model. Current data projects its strong candidature to be developed as anticancer agent.

Carbohydrate derivatives fight against malaria parasite as anti-plasmodial agents.

Malaria, a prevalent fatal disease around the world is caused by Plasmodium sp. and is transmitted by the bite of female Anopheles mosquito. It is leading cause of death in this century among most infectious diseases. Drug resistance was reported for almost every front-line drug against the deadliest species of the malarial parasite, i.e., Plasmodium falciparum. In the evolutionary arms race between parasite and existing arsenals of drugs new molecules having novel mechanism of action is urgently needed to overcome the drug resistance. In this review, we have discussed the importance of carbohydrate derivatives of different class of compounds as possible antimalarials with emphasis on mode of action, rational design, and SAR with improved efficacy. Carbohydrate-protein interactions are increasingly important for medicinal chemists and chemical biologists to understand the pathogenicity of the parasite. Less is known about the carbohydrate-protein interactions and pathogenicity in the Plasmodium parasite. With the increased knowledge on protein-sugar interaction and glycomics of Plasmodium parasites, carbohydrate derivatives can surpass the existing biochemical pathways responsible for drug resistance. The new candidates with novel mode of action will prove to be a potent antimalarial drug candidate without any parasitic resistance.

Screening of Comprehensive Panel of Cultivated and Wild Vigna Species for Resistance to Pulse Beetle, Callosobruchus chinensis L.

Pulses are a key source of dietary proteins in human nutrition. Despite several efforts to increase the production, various constraints, such as biotic and abiotic factors, threaten pulse production by various means. Bruchids (Callosobruchus spp.) are the serious issue of concern, particularly in storage conditions. Understanding host-plant resistance at morphological, biochemical and molecular levels is the best way to minimize yield losses. The 117 mungbean (Vigna radiata L. Wilczek) genotypes, including endemic wild relatives, were screened for resistance against Callosobruchus chinensis; among them, two genotypes, PRR 2008-2 and PRR 2008-2-sel, which belong to V. umbellata (Thumb.), were identified as highly resistant. The expression of antioxidants in susceptible and resistant genotypes revealed that the activity of phenylalanine ammonia lyase (PAL) was upregulated in the highly resistant wild Vigna species and lower in the cultivated susceptible genotypes, along with other biomarkers. Further, the SCoT-based genotyping revealed SCoT-30 (200 bp), SCoT-31 (1200 bp) and SCoT-32 (300 bp) as unique amplicons, which might be useful for developing the novel ricebean-based SCAR markers to accelerate the molecular breeding programme.

Small Carbohydrate Derivatives as Potent Antibiofilm Agents.

Biofilm formation by most pathogenic bacteria is considered as one of the key mechanisms associated with virulence and antibiotic resistance. Biofilm-forming bacteria adhere to the surfaces of biological or implant medical devices and create communities within their self-produced extracellular matrix that are difficult to treat by existing antibiotics. There is an urgent need to synthesize and screen structurally diverse molecules for their antibiofilm activity that can remove or minimize the bacterial biofilm. The development of carbohydrate-based small molecules as antibiofilm agents holds a great promise in addressing the problem of the eradication of biofilm-related infections. Owing to their structural diversity and specificity, the sugar scaffolds are valuable entities for developing antibiofilm agents. In this perspective, we discuss the literature pertaining to carbohydrate-based natural antibiofilm agents and provide an overview of the design, activity, and mode of action of potent synthetic carbohydrate-based molecules.

An Overview on Glyco-Macrocycles: Potential New Lead and their Future in Medicinal Chemistry.

Macrocycles cover a small segment of molecules with a vast range of biological activity in the chemotherapeutic world. Primarily, the natural sources derived from macrocyclic drug candidates with a wide range of biological activities are known. Further evolutions of the medicinal chemistry towards macrocycle-based chemotherapeutics involve the functionalization of the natural product by hemisynthesis. More recently, macrocycles based on carbohydrates have evolved a considerable interest among the medicinal chemists worldwide. Carbohydrates provide an ideal scaffold to generate chiral macrocycles with well-defined pharmacophores in a decorated fashion to achieve the desired biological activity. We have given an overview on carbohydrate-derived macrocycle involving their synthesis in drug design and discovery and potential role in medicinal chemistry.

Synthesis of isatin based N1-alkylated 3-ß-C-glycoconjugated-oxopropylidene oxindoles as potent antiplasmodial agents.

In an attempt to develop new antimalarial drugs, we have synthesized a new class of N-alkylated 3-glycoconjugated-oxopropylidene oxindoles starting from substituted isatins and glucopyranosyl propanone via a well-known cross-aldol reaction followed by dehydration. The newly synthesized compounds were screened for their in vitro antiplasmodial activity, and among all the compounds 9g, 9f, 9b, 8d, 9d, 9c, and 9e displayed potent activity with the IC50 values in the range of 0.1-0.3 µM against Chloroquine (CQ) sensitive Pf3D7 strain, while compounds 9d, 9b, 9e, 8c, 8f, 9c, and 9a have shown promising activity having IC50 values in 0.1-0.4 µM range against CQ resistant PfK1 strain, which is even better than the standard drug chloroquine with IC50 value of 0.5 µM.

Identification of dual role of piperazine-linked phenyl cyclopropyl methanone as positive allosteric modulator of 5-HT2C and negative allosteric modulator of 5-HT2B receptors.

Allosteric modulators of G-protein-coupled receptors have lately gained significant traction in drug discovery. Recent studies have shown that allosteric modulation of serotonin 2C receptor (5-HT2C) as a viable strategy for the treatment of various central nervous system (CNS) disorders. Considering the critical role of 5-HT2C in the modulation of appetite, a selective positive allosteric modulator (PAM) of 5-HT2C offers a new opportunity for anti-obesity therapeutic development. In this study, phenyl cyclopropyl-linked N-heterocycles were synthesized and evaluated at 5-HT2C for agonist and PAM activity. Our study shows that imidazole linked phenyl cyclopropyl methanones has PAM activity on both 5-HT2C and serotonin 2B receptor (5-HT2B). Interestingly, piperazine linked phenyl cyclopropyl methanones (58) was active as PAM of 5-HT2C (increased the Emax of 5-HT to 139%), and as negative allosteric modulator (NAM) of 5-HT2B (decreases EC50 of 5-HT 10 times without affecting Emax). Similar effect of compound 58 was observed with synthetic orthosteric agonist lorcaserin on 5-HT2B. Molecular docking study revealed that all active compounds were binding to the predicted allosteric site on 5-HT2C and shared a common interacting residues. Finally, compound 58 suppressed food intake in Sprague Dawley (SD) rats similar to lorcaserin after i.c.v. administration. Therefore, these results suggest that piperazine moiety is essential for dual activity (PAM & NAM) of compounds 58, and supports the hypothesis of 5-HT2C PAM for the treatment of obesity similar to the full agonist.

Novel Tetrahydroquinazolinamines as Selective Histamine 3 Receptor Antagonists for the Treatment of Obesity.

The histamine 3 receptor (H3R) is a presynaptic receptor, which modulates several neurotransmitters including histamine and various essential physiological processes, such as feeding, arousal, cognition, and pain. The H3R is considered as a drug target for the treatment of several central nervous system disorders. We have synthesized and identified a novel series of 4-aryl-6-methyl-5,6,7,8-tetrahydroquinazolinamines that act as selective H3R antagonists. Among all the synthesized compounds, in vitro and docking studies suggested that the 4-methoxy-phenyl-substituted tetrahydroquinazolinamine compound 4c has potent and selective H3R antagonist activity (IC50 < 0.04 µM). Compound 4c did not exhibit any activity on the hERG ion channel and pan-assay interference compounds liability. Pharmacokinetic studies showed that 4c crosses the blood brain barrier, and in vivo studies demonstrated that 4c induces anorexia and weight loss in obese, but not in lean mice. These data reveal the therapeutic potential of 4c as an anti-obesity candidate drug via antagonizing the H3R.

Bilateral medial rectus palsy due to midbrain infarction following concussion head injury.

Here, we report a rare case of bilateral medial rectus palsy following closed head injury. An adult male had an accidental fall which rendered him unconscious. This was followed by diplopia and restricted ocular motility. He received supportive medical therapy. He was examined for systemic medical and ophthalmic findings. Routine laboratory tests and imaging techniques were employed as per the symptoms. Diffusion-weighted imaging on magnetic resonance imaging proved it to be a rare presentation of small bilateral midbrain infarct. He recovered fully after 8 months.

Synthesis and antiplasmodial activity of purine-based C-nucleoside analogues.

A series of homologous C-nucleoside mimics have been synthesized via an efficient and facile synthetic protocol involving the conjugate addition of purine to sugar derived olefinic ester in good yields. The synthesized compounds were evaluated for their antiplasmodial activity in vitro against both the CQ-sensitive and resistant strains of P. falciparum. Interestingly, all the synthesized nucleoside analogs exhibited an IC50 of <5 µM, while compounds 22a, 23a, and 23b showed promising antiplasmodial activity with an IC50 of 1.61, 0.88, and 1.01 µM against the CQ-sensitive Pf3D7 strain and 1.14, 1.01, and 2.57 µM against the CQ-resistant PfK1 strain, respectively.

Identification of ß-Amino alcohol grafted 1,4,5 trisubstituted 1,2,3-triazoles as potent antimalarial agents.

In a quest to discover new drugs, we have synthesized a series of novel ß-amino alcohol grafted 1,2,3-triazoles and screened them for their in vitro antiplasmodial and in vivo antimalarial activity. Among them, compounds 16 and 25 showed potent activity against chloroquine-sensitive (Pf3D7) strain with IC50 of 0.87 and 0.3 µM respectively, while compounds 7 and 13 exhibited better activity in vitro than the reference drug against chloroquine-resistance strain (PfK1) with IC50 of 0.5 µM each. Compound 25 showed 86.8% in vivo antimalarial efficacy with favorable pharmacokinetic parameters. Mechanistic studies divulged that potent compounds significantly boosted p53 protein levels to exhibit the antimalarial activity.