Furanocoumarins promote proteasomal degradation of viral HBx protein and down-regulate cccDNA transcription and replication of hepatitis B virus.

Nucleot(s)ide analogues, the current antiviral treatments against chronic hepatitis B (CHB) infection, are non-curative due to their inability to eliminate covalently closed circular DNA (cccDNA) from the infected hepatocytes. Preclinical studies have shown that coumarin derivatives can effectively reduce the HBV DNA replication. We evaluated the antiviral efficacy of thirty new coumarin derivatives in cell culture models for studying HBV. Furanocoumarins Fc-20 and Fc-31 suppressed the levels of pre-genomic RNA as well as cccDNA, and reduced the secretion of virions, HBsAg and HBeAg. The antiviral efficacies of Fc-20 and Fc31 improved further when used in combination with the hepatitis B antiviral drug Entecavir. There was a marked reduction in the intracellular HBx level in the presence of these furanocoumarins due to proteasomal degradation resulting in the down-regulation of HBx-dependent viral genes. Importantly, both Fc-20 and Fc-31 were non-cytotoxic to cells even at high concentrations. Further, our molecular docking studies confirmed a moderate to high affinity interaction between furanocoumarins and viral HBx via residues Ala3, Arg26 and Lys140. These data suggest that furanocoumarins could be developed as a new therapeutic for CHB infection.

QcrB in Mycobacterium tuberculosis: The new drug target of antitubercular agents.

Drug-resistance in mycobacterial infections is a major global health problem that leads to high mortality and socioeconomic pressure in developing countries around the world. From finding new targets to discovering novel chemical scaffolds, there is an urgent need for the development of better approaches for the cure of tuberculosis. Recently, energy metabolism in mycobacteria, particularly the oxidative phosphorylation pathway of cellular respiration, has emerged as a novel target pathway in drug discovery. New classes of antibacterials which target oxidative phosphorylation pathway either by interacting with a protein or any step in the pathway of oxidative phosphorylation can combat dormant mycobacterial infections leading to shortening of tuberculosis chemotherapy. Adenosine triphosphate synthase is one such recently discovered target of the newly approved antitubercular drug bedaquiline. Cytochrome bcc is another new target of the antitubercular drug candidate Q203, currently in phase II clinical trial. Research suggests that b subunit of cytochrome bcc, QcrB, is the target of Q203. The review article describes the structure, function, and importance of targeting QcrB throwing light on all chemical classes of QcrB inhibitors discovered to date. An understanding of the structure and function of validated targets and their inhibitors would enable the development of new chemical entities.

3D QSAR studies on amphiphilic indoles for antimycobacterial activity.

A persistent infection prolongs treatment duration and also enhances the chance of resistance development against antibiotics. Recently, a class of amphiphilic indole derivatives was discovered exhibiting bactericidal activity against both growing and nongrowing Mycobacterium bovis BCG (M. bovis BCG). These antibacterials are suggested to disturb the integrity and functioning of the cell membrane, a property that can help eradicate persistent organisms. This study article describes field-based three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of 79 amphiphilic indole derivatives. The aim of this QSAR study is to optimize this class of compounds for the development of more potent antimycobacterial agents. The results obtained indicate that steric interactions are crucial for antimycobacterial activity, while hydrogen bond donor groups participate negligibly in activity. The derived 3D-QSAR models showed acceptable r2 (0.91) and q2 (0.91) with a root mean squared error (RMSE) of 0.08. The models were cross-validated using the leave-one-out method. Applying the same QSAR model to another congeneric series of amphiphilic indoles externally validated the QSAR model. The model could appreciably predict the activity (pMIC50 ) of this congeneric series of amphiphilic indoles, with an RMSE of 0.49, indicating the robustness of the model and its efficiency in predicting the potentially active compounds.

An overview of new antitubercular drugs, drug candidates, and their targets.

The causative agent of tuberculosis (TB), Mycobacterium tuberculosis and more recently totally drug-resistant strains of M. tuberculosis, display unique mechanisms to survive in the host. A four-drug treatment regimen was introduced 40 years ago but the emergence of multidrug-resistance and more recently TDR necessitates the identification of new targets and drugs for the cure of M. tuberculosis infection. The current efforts in the drug development process are insufficient to completely eradicate the TB epidemic. For almost five decades the TB drug development process remained stagnant. The last 10 years have made sudden progress giving some new and highly promising drugs including bedaquiline, delamanid, and pretomanid. Many of the candidates are repurposed compounds, which were developed to treat other infections but later, exhibited anti-TB properties also. Each class of drug has a specific target and a definite mode of action. These targets are either involved in cell wall biosynthesis, protein synthesis, DNA/RNA synthesis, or metabolism. This review discusses recent progress in the discovery of newly developed and Food and Drug Administration approved drugs as well as repurposed drugs, their targets, mode of action, drug-target interactions, and their structure-activity relationship.

N-Substituted aminoquinoline-pyrimidine hybrids: Synthesis, in vitro antimalarial activity evaluation and docking studies.

A series of novel molecular hybrids based on 4-aminoquinoline-pyrimidine were synthesized and examined for their antimalarial activity. Most of the compounds were found to have potent in vitro antimalarial activity against both CQ-sensitive D6 and CQ-resistant W2 strains of P. falciparum. The active compounds have no considerable cytotoxicity against the mammalian VERO cell lines. Twenty three compounds displayed better antimalarial activity against CQ-resistant strain W2 with IC50 values in the range 0.0189-0.945 µM, when compared with standard drug chloroquine. The best active compound 7d was studied for heme binding so as to find the primary mode of action of these hybrid molecules. Compound 7d was found to form a stable 1:1 complex with hematin as determined by its Job's plot which suggests that heme may be a probable target of these molecules. Docking studies performed with Pf-DHFR exhibited good binding interactions in the active site. The pharmacokinetic properties of some active compounds were also analysed using ADMET prediction.

N-Piperonyl substitution on aminoquinoline-pyrimidine hybrids: Effect on the antiplasmodial potency.

A series of 4-aminoquinoline-piperonyl-pyrimidine hybrids were synthesized with the aim of identifying compounds with enhanced antimalarial activity. All the synthesized molecules were evaluated in vitro against cultured Plasmodium falciparum W2 and D6 strains and exhibited potent antiplasmodial activities with IC50 values in the range of 0.02-5.16 µM. Out of the 22 synthesised hybrids, 12 were found to be better (up to eight-fold more active) than chloroquine (CQ), particularly against the CQ-resistant W2 strain of P. falciparum with no significant cytotoxicity towards the mammalian cells. Mechanistic studies reveal that these compounds bind with heme and computational docking studies showed good docking interactions within the active site of Pf-DHFR.

Synthesis, antimalarial activity, heme binding and docking studies of N-substituted 4-aminoquinoline-pyrimidine molecular hybrids.

A series of novel N-substituted 4-aminoquinoline-pyrimidine hybrids have been synthesized via simple and economic route and evaluated for their antimalarial activity. Most compounds showed potent antimalarial activity against both CQ-sensitive and CQ-resistant strains with high selectivity index. All the compounds were found to be non-toxic to the mammalian cell lines. The most active compound 7b was analysed for heme binding activity using UV-spectrophotometer. Compound was found to interact with heme and a complex formation between compound and heme in a 1:1 stoichiometry ratio was determined using job plots. The interaction of these hybrids was also investigated by the molecular docking studies in the binding site of wild type Pf-DHFR-TS and quadruple mutant Pf-DHFR-TS. The pharmacokinetic property analysis of best active compounds was also studied by ADMET prediction.