Synthesis and anti-HBV activity of carbocyclic nucleoside hybrids with salient features of entecavir and aristeromycin.

Modified carbocyclic nucleosides () constituting 7-deazapurine, 4'-methyl, exocyclic double bond and 2',3'-hydroxy were synthesized. NOE and X-ray studies of confirmed the α-configuration of 4'-methyl. The anti-HBV assay demonstrated (IC = 3.

Discovery of 2-isoxazol-3-yl-acetamide analogues as heat shock protein 90 (HSP90) inhibitors with significant anti-HIV activity.

The recent burst of explorations on heat shock protein 90 (HSP90) in virus research supports its emergence as a promising target to overcome the drawbacks of current antiviral therapeutic regimen. In continuation of our efforts towards the discovery of novel anti-retroviral molecules, we designed, synthesized fifteen novels 2-isoxazol-3-yl-acetamide based compounds (2a-o) followed by analysis of their anti-HIV activity and cytotoxicity studies. 2a-b, 2e, 2j, and 2l-m were found to be active with inhibitory potentials >80% at their highest non-cytotoxic concentration (HNC).

First Insight on Small Molecules as Cardiac Calsequestrin Stabilizers.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations of cardiac calsequestrin (CASQ2) that impair its characteristic ability of Ca-induced polymerization-depolymerization. However, stabilizing the CASQ2 polymer by pharmacological agents to treat CPVT has not been reported so far. Here, we tested whether small molecules can stabilize CASQ2 polymers.

Rhodium catalyzed stereospecific reductive carbocyclization of 1,6-enynes and synthesis of 4'-methyl-6'-substituted aristeromycins.

The need of long-term treatment for chronic HBV, emergence of drug-resistant viruses and inefficiency of currently approved therapies to eliminate covalently closed circular DNA (cccDNA), mandates identification of potent and selective inhibitors of HBV replication with novel mechanisms of action. Entecavir, a carbocyclic guanosine nucleoside analog, is the most potent inhibitor of HBV replication on the market. Moreover, the naturally occurring carbocyclic nucleosides aristeromycin are known for their wide range of antiviral activities.

Synthesis and Anti-HCV Activity of 4-Methoxy-7H-Pyrrolo[2,3-d] Pyrimidine Carbocyclic Nucleosides.

The present study includes the exploration of new possible nucleoside mimetics based on 4-methoxy-7H-pyrrolo[2,3-d]pyrimidine carbocyclic nucleosides (4a-g), which were synthesized by 10-15 synthetic steps and characterized adequately. We report the anti-HCV activities and cytotoxicities of 4a-g. Compound 4a was analyzed by single crystal X-ray diffraction which showed some puckering in the cyclopentene ring with a 2'-endo conformation and anti-base disposition (χ = -125.

Regioselective Synthesis of Pyrazolo[3,4-D]Pyrimidine Based Carbocyclic Nucleosides as Possible Antiviral Agent.

Carbocyclic nucleosides are considered as nucleoside mimetic having high therapeutic potentials, however diverse exploration is still limited due to their synthetic difficulties. The major challenges are associated with the preparation of new base and carbocyclic sugar key intermediates. The modified base may provide conformational advantage to achieve better nucleoside mimetics and may also help in increasing the drug-like properties.

Synthesis of multi ring-fused imidazo [1,2- a]isoquinoline-based fluorescent scaffold as anti-Herpetic agent.

Background: Natural product-inspired synthesis is a key incorporation in modern diversity-oriented synthesis to yield biologically novel scaffold. Inspired by β-carboline fused system, we have designed molecules with multi ring fused scaffold by modifying the tricyclic pyrido[3,4- b]indole ring with imidazo[1,2- a]isoquinoline.

Methods: A highly convergent approach with new C-N and C-C bond formation to synthesize multiring fused complex scaffold imidazo[1,2- a]isoquinolinies as fluorophores.

Synthesis and anti-HCV determinant motif identification in pyranone carboxamide scaffold.

Hepatitis C Virus exhibits high genetic diversity. The current treatment for genotype-1 with ∼80% sustained virologic responses is a combination of pegylated interferon, ribavirin and boceprevir/telaprevir/simeprevir which is associated with several side effects and need close monitoring. Therefore, novel therapies are invited for safer and more efficient treatment.

Synthesis and Anti-HCV Activity of 4-Hydroxyamino α-Pyranone Carboxamide Analogues.

High genetic variability in hepatitis C virus (HCV), emergence of drug resistant viruses and side effects demand the requirement for development of new scaffolds to show an alternate mechanism. Herein, we report discovery of new scaffold I based on 4-hydroxyamino α-pyranone carboxamide as promising anti-HCV agents. A comprehensive structure-activity relationship (SAR) was explored with several newly synthesized compounds.

Skeletal hybridization and PfRIO-2 kinase modeling for synthesis of α-pyrone analogs as anti-malarial agent.

The pharmacophoric hybridization and computational design approach were applied to generate a novel series of α-pyrone analogs as plausible anti-malarial lead candidate. A putative active site in flexible loop close to wing-helix domain of PfRIO2 kinase was explored computationally to understand the molecular basis of ligand binding. All the synthesized molecules (3a-g) exhibited in vitro antimalarial activity.

A conformational mimetic approach for the synthesis of carbocyclic nucleosides as anti-HCV leads.

Computer-aided approaches coupled with medicinal chemistry were used to explore novel carbocyclic nucleosides as potential anti-hepatitis C virus (HCV) agents. Conformational analyses were carried out on 6-amino-1H-pyrazolo[3,4-d]pyrimidine (6-APP)-based carbocyclic nucleoside analogues, which were considered as nucleoside mimetics to act as HCV RNA-dependent RNA polymerase (RdRp) inhibitors. Structural insight gained from the modeling studies revealed the molecular basis behind these nucleoside mimetics.

Targeting peroxisome proliferator-activated receptor gamma for generation of antidiabetic drug.

The incidence of Diabetes Mellitus (DM) has increased to alarming levels not only in developed countries but also in developing and underdeveloped countries. Scientific data have made it clear by now that patients with DM are predisposed to many other diseases. One of the worst associations of DM is with obesity and the number of DM patients with obesity is increasing at a very fast pace due to dramatic change in life style around the world in last few decades.

Identification of calcium binding sites on calsequestrin 1 and their implications for polymerization.

Biophysical studies have shown that each molecule of calsequestrin 1 (CASQ1) can bind about 70-80 Ca(2+) ions. However, the nature of Ca(2+)-binding sites has not yet been fully characterized. In this study, we employed in silico approaches to identify the Ca(2+) binding sites and to understand the molecular basis of CASQ1-Ca(2+) recognition.

Structure based medicinal chemistry approach to develop 4-methyl-7-deazaadenine carbocyclic nucleosides as anti-HCV agent.

The structure-based approaches were implemented to design and rationally select the molecules for synthesis and anti-HCV activity evaluation. The systematic structure-activity relationships of previously discovered molecules (types I, II, III) were analyzed to design new molecules (type IV) by bioisosteric replacement of the amino group. The ligand conformation, binding mode studies and drug like properties were major determinant for selection of molecules for final synthesis.

Molecular and structural insight into plasmodium falciparum RIO2 kinase.

Among approximately 65 kinases of the malarial genome, RIO2 (right open reading frame) kinase belonging to the atypical class of kinase is unique because along with a kinase domain, it has a highly conserved N-terminal winged helix (wHTH) domain. The wHTH domain resembles the wing like domain found in DNA binding proteins and is situated near to the kinase domain. Ligand binding to this domain may reposition the kinase domain leading to inhibition of enzyme function and could be utilized as a novel allosteric site to design inhibitor.

Structure based molecular design, synthesis and biological evaluation of α-pyrone analogs as anti-HSV agent.

Several options for treating Herpes Simplex Virus type 1 and type 2 are available. However, non-specific inhibition and drug resistance warrants the discovery of new anti-herpetic compounds with better therapeutic profile or different mode of action. The non-nucleoside inhibitors of HSV DNA polymerase target the site that is less important for the binding of a natural nucleoside or nucleoside inhibitors.

Probing cationic selectivity of cardiac calsequestrin and its CPVT mutants.

CASQ (calsequestrin) is a Ca2+-buffering protein localized in the muscle SR (sarcoplasmic reticulum); however, it is unknown whether Ca2+ binding to CASQ2 is due to its location inside the SR rich in Ca2+ or due to its preference for Ca2+ over other ions. Therefore a major aim of the present study was to determine how CASQ2 selects Ca2+ over other metal ions by studying monomer folding and subsequent aggregation upon exposure to alkali (monovalent), alkaline earth (divalent) and transition (polyvalent) metals. We additionally investigated how CPVT (catecholaminergic polymorphic ventricular tachycardia) mutations affect CASQ2 structure and its molecular behaviour when exposed to different metal ions.

Synthesis and anti-hepatitis B virus and anti-hepatitis C virus activities of 7-deazaneplanocin A analogues in vitro.

A series of 7-deazaneplanocin A (7-DNPA, 2) analogues were synthesized and evaluated for in vitro antiviral activity against HBV and HCV. The syntheses of target carbocyclic nucleosides were accomplished via a convergent procedure. 7-Substitutions were introduced by using 7-substituted-7-deaza heterocyclic base precursors (F, Cl, Br, and I) or via substitution reactions after the synthesis of the carbocyclic nucleosides.

4,6-bis(methylsulfanyl)-1-(4-phenoxybutyl)-1H-pyrazolo[3,4-d]pyrimidine.

The molecular structure of the title compound, C(17)H(20)N(4)OS(2), does not show any intramolecular aromatic pi-pi interactions, but the crystal packing reveals the presence of intermolecular C--H...

Unusual molecular conformation in dissymmetric propylene-linker compounds containing pyrazolo[3,4-d]pyrimidine and phthalimide moieties.

The crystal structure of 4,6-bis(methylsulfanyl)-1-phthalimidopropyl-1H-pyrazolo[3,4-d]pyrimidine, C(18)H(17)N(5)O(2)S(2), (VI), reveals an unusual folded conformation due to an apparent intramolecular C-H.pi interaction between the 6-methylsulfanyl and phenyl groups. However, the closely related compound 6-methylsulfanyl-1-phthalimidopropyl-4-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine, C(21)H(22)N(6)O(2)S, (VII), exhibits a fully extended structure, devoid of any intramolecular C-H.