Chandra S. Azad

Copper-catalysed regioselective azidation of arenes by C–H activation directed by pyridine

A novel and efficient copper-catalysed pyridine directed ortho-azidation of arenes has been developed using safe and stable benzotriazole sulphonyl azide as the azidating agent. A variety of organo azides have been synthesized with electron donor and withdrawing groups, thereby the azide products can be easily transformed into assorted functionalities.

Novel Glycoconjugate of 8-Fluoro Norfloxacin Derivatives as Gentamicin-resistant Staphylococcus aureus Inhibitors: Synthesis and Molecular Modelling Studies

Antibiotic resistance has been the subject of interest in clinical practice due to high prevalence of antibiotic‐resistant pathogenic organisms. In view of the prevalence of lesser resistance in antibiotics belonging to aminoglycoside class of compounds viz. Food and Drug Administration‐approved gentamicin for the treatment of Staphylococcus infections, which also has instances of resistance in the clinical isolates of Staphylococcus aureus, a series of novel glycoconjugates of 8‐fluoro norfloxacin analogues with high regio‐selectivity by employing copper (I)‐catalyzed 1, 3‐dipolar cycloaddition of 1‐O‐propargyl monosaccharides has been synthesized and evaluated for the antibacterial activity against gentamicin resistance Staphylococcus aureus. Among these compounds, the compound 10g showed better antibacterial activity (MIC = 3.12 μg/ml) than gentamicin (Escherichia coli (12.5 μg/ml), Staphylococcus aureus (6.25 μg/ml) and Klebsiella pneumonia (6.25 μg/ml), including gentamicin resistant (>50 μg/ml) strain in vitro). The docking studies suggest DNA gyrase of Staphylococcus aureus as a probable target for the antibacterial action of compound 10g.

Operative conversions of 3-carboxy-4-quinolones into 3-nitro-4-quinolones via ipso-nitration: potential antifilarial agents as inhibitors of Brugia malayi thymidylate kinase

An efficient, cost effective and green methodology for ipso nitration in the synthesis of the 3-nitro derivative of 3-carboxy 4-quinolones has been developed by the quantitative use of copper acetate and silver nitrate in water. The observed regioselectivity of nitration is explained by the DFT calculations. Three of these compounds with IC50 values (2.9–3.4 μmol) against Brugia malayi thymidylate kinase may be good antifilarial agents as also evidenced by molecular docking studies.

An operational transformation of 3-carboxy-4-quinolones into 3-nitro-4-quinolones via ipso -nitration using polysaccharide supported copper nanoparticles: synthesis of 3-tetrazolyl bioisosteres of 3-carboxy-4-quinolones as antibacterial agents

Chitosan supported Cu nano-particles have been synthesized, and utilized for the synthesis of 3-nitro-4-quinolones from 3-carboxy-4-quinolones via ipso nitration. The synthesized 3-nitro derivatives of 4-quinolones were successfully converted into their 3-tetrazolyl bioisosteres which showed increased antibacterial activity as compared to the standard ciprofloxacin.

Stereoconvergent synthesis of 1-deoxynojirimycin isomers by using the 3 component 4 centred Ugi reaction

A new reductive cyclization/Ugi multicomponent reaction sequence for the synthesis of 1-deoxyallonojirimycin and 1-deoxyaltronojirimycin has been developed. The method was successfully applied to the azido-hemiacetal derived from commercially available D-ribose. The very selective reagents were used for the synthesis of Ugi bis-amides which were sub sequentially hydrolysed to iminosugars.

Organocatalyzed asymmetric Michael addition by an efficient bifunctional carbohydrate–thiourea hybrid with mechanistic DFT analysis

A series of thiourea based bifunctional organocatalysts having d-glucose as a core scaffold were synthesized and examined as catalysts for the asymmetric Michael addition reaction of aryl/alkyl trans-β-nitrostyrenes over cyclohexanone and other Michael donors having active methylene. Excellent enantioselectivities (<95%), diastereoselectivities (<99%), and yields (<99%) were attained under solvent free conditions using 10 mol% of 1d0. The obtained results were explained through DFT calculations using the B3LYP/6-311G(d,p)//B3LYP/6-31G(d) basic set. The QM/MM calculations revealed the role of cyclohexanone as a solvent as well as reactant in the rate determining step imparting 31.91 kcal mol-1 of energy towards the product formation.

Novel Imbricatolic acid derivatives as protein tyrosine phosphatase-1B inhibitors: Design, synthesis, biological evaluation and molecular docking.

Protein tyrosine phosphatase (PTP-1B) antagonizes insulin signaling and is a potential therapeutic target for insulin resistance associated with obesity and type 2 diabetes. To find potential PTP-1B inhibitors, derivatives of Imbricatolic acid (1) have been synthesized by introducing various nitrogenous functionalities at C-15 and C-19 positions. They were evaluated for PTP-1B enzyme inhibition activity. Compounds 3, 6, 14, and 15 exhibited promising PTP-1B inhibitory activity at 10 μM concentrations with IC50 6.3, 6.8, 7.0 and 7.8 values, respectively. Structure activity relationship and molecular docking studies of these derivatives demonstrated that the integrity of the polar substituents were important for significant PTP-1B inhibitory activity. The Imbricatolic acid and active derivatives in this study might represent a starting point for development of new potential PTP-1B inhibitors.

Synthesis of Primaquine Glyco-conjugates as potential tissue-schizontocidal antimalarial agents.

Primaquine (PQ) is the only drug used to prevent relapse of malaria due to P. vivax and P. ovale, by eradicating the dormant liver form of the parasite (hypnozoites). The side‐effects associated with PQ limits is uses in treatment of malaria. To overcome the premature oxidative deamination and to increase the life span of drug in the biological system, the novel glyco‐conjugates of PQ were synthesized by coupling of primaquine with hexoses in phosphate buffer. The saccharide part of the hybrid molecules thought to direct the drug to the liver, where hypnozoites resides. All the synthesized compounds were fully characterized and evaluated for their radical curative activities. The three compounds viz glucoside (15a), galactoside (15b) and mannoside (15c) with high activity were tested for their activity in rhesus monkeys where the most active compound 15b showed twofold activity (100% radical curative activity at 1.92 mmol/kg) than the standard drug PQ diphosphate (3.861 mmol/kg). It is proposed that results from these studies may be advantageous to develop a new potent tissue schizonticide antimalarial compound.

Neglected Tropical Bacterial Diseases

Neglected tropical diseases (NTDs) belong to a diverse group of communicable diseases caused by pathogens including helminthes, protozoa, bacteria, and viruses. The NTDs prevail in tropical and subtropical conditions in 149 countries and affect billions of people, resulting in an economic burden of billions of dollars every year. The major neglected tropical bacterial diseases (NTBDs) are Leprosy, Buruli ulcer, and Trachoma. Leprosy and Buruli ulcer are caused by members of the Mycobacterium genus viz M. leprae and M. ulcerans and are responsible for the most severe medical impact in the tropics. Trachoma is the result of infection of the eye with Chlamydia trachomatis and it is responsible for the visual impairment of about 1.8 million people, of whom 0.5 million are irreversibly blind. In this chapter the above major NTBDs are discussed in terms of their epidemiology, pathogenic vector, metabolism, genomic and immunological analysis, classification, treatment, resistance, and vaccine development.