Antimicrobial potential of quaternary phosphonium salt compounds: a review.

Given that mitochondrial dysregulation is a biomarker of many cancers, cationic quaternary phosphonium salt (QPS) conjugation is a widely utilized strategy for anticancer drug design. QPS-conjugated compounds exhibit greater cell permeation and accumulation in negatively charged mitochondria, and thus, show enhanced activity. Phylogenetic similarities between mitochondria and bacteria have provided a rationale for exploring the antibacterial properties of mitochondria-targeted compounds.

The expanding repertoire of covalent warheads for drug discovery.

The reactive functionalities of drugs that engage in covalent interactions with the enzyme/receptor residue in either a reversible or an irreversible manner are called 'warheads'. Covalent warheads that were previously neglected because of safety concerns have recently gained center stage as a result of their various advantages over noncovalent drugs, including increased selectivity, increased residence time, and higher potency. With the approval of several covalent inhibitors over the past decade, research in this area has accelerated.

Elemental exchange: Bioisosteric replacement of phosphorus by boron in drug design.

Continuous efforts are being directed toward the employment of boron in drug design due to its advantages and unique characteristics including a plethora of target engagement modes, lower metabolism, and synthetic accessibility, among others. Phosphates are components of multiple drug molecules as well as clinical candidates, since they play a vital role in various biochemical functions, being components of nucleotides, energy currency- ATP as well as several enzyme cofactors. This review discusses the unique chemistry of boron functionalities as phosphate bioisosteres - "the boron-phosphorus elemental exchange strategy" as well as the superiority of boron groups over other commonly employed phosphate bioisosteres.

Mitochondriotropic Derivative of Ethyl Ferulate, a Dietary Phenylpropanoid, Exhibits Enhanced Cytotoxicity in Cancer Cells via Mitochondrial Superoxide-Mediated Activation of JNK and AKT Signalling.

Specific targeting of anti-cancer drugs to mitochondria is an emerging strategy to enhance cancer cell killing whilst simultaneously overcoming the problem of drug resistance, low bioavailability and limited clinical success of natural products. We have synthesized a mitochondria targeted derivative of Ethyl Ferulate (EF, a naturally occurring ester of ferulic acid), by conjugating it with triphenylphosphonium ion and compared its cytotoxicity with the parent molecule. Mito-Ethyl Ferulate (M-EF) was found to be more potent than EF (~ 400-fold) in inhibiting the growth of A549 and MCF-7 cells and suppressing the clonogenic potential of A549 cells.

Role of calcium dysregulation in Alzheimer's disease and its therapeutic implications.

The increasing incidence of Alzheimer's disease (AD) coupled with the lack of therapeutics to address the underlying pathology of the disease has necessitated the need for exploring newer targets. Calcium dysregulation represents a relatively newer target associated with AD. Ca serves as an important cellular messenger in neurons.

Identification of bicyclic compounds that act as dual inhibitors of Bcl-2 and Mcl-1.

Elevated expression of anti-apoptotic proteins, such as Bcl-2 and Mcl-1 contributes to poor prognosis and resistance to current treatment modalities in multiple cancers. Here, we report the design, synthesis and characterization of benzimidazole chalcone and flavonoid scaffold-derived bicyclic compounds targeting both Bcl-2 and Mcl-1 by optimizing the structural differences in the binding sites of both these proteins. Initial docking screen of Bcl-2 and Mcl-1 with pro-apoptotic protein Bim revealed possible hits with optimal binding energies.

Biochemical aspects of hemoglobin-xenobiotic interactions and their implications in drug discovery.

Hemoglobin, a homodimeric globular protein, is found predominantly in red blood cells and in a small amount in blood plasma. Along with binding to certain native molecules, it also interacts with various xenobiotics. The present review aims at studying these interactions and the resultant tangible impact on the structure and function of the protein if any.

Antituberculosis activity of polyphenols of .

Background: Polyphenols have been studied for their potential involvement in the prevention of various chronic diseases as well as for their antimicrobial potential. The crude extracts of arecanut have been reported to have antiinfective properties. We aimed to explore the endosperm of Areca catechu (arecanut) for the extraction of polyphenol components and to study the antituberculosis activity of these polyphenol against Mycobacterium tuberculosis H37Rv.

Mutations in SARS-CoV-2 nsp7 and nsp8 proteins and their predicted impact on replication/transcription complex structure.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA-dependent RNA polymerase (RdRp) has been identified to be a mutation hot spot, with the P323L mutation being commonly observed in viral genomes isolated from North America. RdRp forms a complex with nonstructural proteins nsp7 and nsp8 to form the minimal replication/transcription machinery required for genome replication. As mutations in RdRp may affect formation of the RdRp-nsp7-nsp8 supercomplex, we analyzed viral genomes to identify mutations in nsp7 and nsp8 protein sequences.

Exploring the potential of pyrazoline containing molecules as Aβ aggregation inhibitors in Alzheimer's disease.

Objectives Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease in which one of the most prominent pathological features is accumulation of amyloid (Aβ) plaques. This occurs due to the process of aggregation from monomeric to polymeric forms of Aβ peptide and thus represents one of the attractive targets to treat AD. Methods After initial evaluation of a set of molecules containing N-acetylpyrazoline moiety flanked by aromatic rings on both sides as Aβ aggregation inhibitors, the most potent molecules were further investigated for mechanistic insights.

3-(5-Nitrofuran-2-yl)prop-2-en-1-one Derivatives, with Potent Antituberculosis Activity, Inhibit A Novel Therapeutic Target, Arylamine -acetyltransferase, in Mycobacteria.

In this study, the inhibitory potential of 3-(5-nitrofuran-2-yl)prop-2-en-1-one derivatives was evaluated against a panel of bacteria, as well as mammalian cell lines to determine their therapeutic index. In addition, we investigated the mechanism of antibiotic action of the derivatives to identify their therapeutic target. We discovered compound to be an extremely potent inhibitor of H37Rv growth (MIC: 0.

Tackling SARS-CoV-2: proposed targets and repurposed drugs.

The SARS-CoV-2 pandemic, declared as a global health emergency by the WHO in February 2020, has currently infected more than 6 million people with fatalities near 371,000 and increasing exponentially, in absence of vaccines and drugs. The pathogenesis of SARS-CoV-2 is still being elucidated. Identifying potential targets and repurposing drugs as therapeutic options is the need of the hour.

In silico modeling of functionalized poly(methylvinyl ether/maleic acid) for controlled drug release in the ocular milieu.

Controlling structurally defined properties of drug-bound macromolecules such as surface adhesion and interaction with endogenous proteins in the surrounding environment using prior data from computer-assisted simulation can be of great use in designing controlled release macromolecular therapeutic systems. In this paper, we describe experimental correlation of real-time properties of a polymer with pendant drug molecules, with predicted values obtained from studying in silico molecular interactions of this polymer with ocular surface proteins (mucin) for formulating an ophthalmic in situ gel. Mucoretention of the drug (norfloxacin) within the eye sac is closely associated with binding interactions occurring on the ocular surface, and covalent association of the drug with the mucoadhesive polymer, poly(methylvinyl ether/maleic acid), can largely reduce dosing frequency eliciting prolonged antibacterial action much required in treating conjunctival infections.

Network topology of LMWG cross-linked xyloglucan hydrogels for embedding hydrophobic nanodroplets: mechanistic insight and molecular dynamics.

Indigenous polymers have functional implications in biomedicine due to the presence of an inherent favorable structural architecture that supports hydrogel formation. In this study, we present the molecular level characterization of xyloglucan hydrogels using experimental and molecular simulation methods. We studied supramolecular self-assembly of tamarind seed-derived xyloglucan induced by low molecular weight gelators to form dense networks and rationalized its capabilities as a multifunctional and multiresponsive matrix for holding hydrophobic nanometric oleic acid globules intact for extended periods, preventing coalescence triggered instability using computational methods and imaging.

Targeting cancer's Achilles' heel: role of BCL-2 inhibitors in cellular senescence and apoptosis.

Members of the antiapoptotic BCL-2 proteins are involved in tumor growth, progression and survival, and are also responsible for chemoresistance to conventional anticancer agents. Early efforts to target these proteins yielded some active compounds; however, newer methodologies involving structure-based drug design, Nuclear Magnetic Resonance (NMR)-based screening and fragment-based screening yielded more potent compounds. Discovery of specific as well as nonspecific inhibitors of this class of proteins has resulted in great advances in targeted chemotherapy and decrease in chemoresistance.

Exploration of 5-(5-nitrothiophen-2-yl)-4,5-dihydro-1H-pyrazoles as selective, multitargeted antimycobacterial agents.

We report the biological evaluation of 5-(5-nitrothiophen-2-yl)-4,5-dihydro-1H-pyrazole derivatives against bacteria, eukaryotic cell lines and the assessment of their mechanisms of action to determine their prospects of being developed into potent antituberculosis agents. The compounds were evaluated for their antibacterial property against Mycobacterium tuberculosis H37Rv, multidrug-resistant M. tuberculosis, Mycobacterium bovis BCG, Mycobacterium aurum, Escherichia coli, and Staphylococcus aureus using high-throughput spot-culture growth inhibition assay.

Synthesis and mycobacterial evaluation of 5-substituted-6-acetyl-2-amino-7-methyl-5,8-dihydropyrido-[2,3-d]pyrimidin-4(3H)-one derivatives.

5-Substituted-6-acetyl-2-amino-7-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-4(3H)-one derivatives were synthesized and evaluated against Mycobacterium tuberculosis H37Rv, Mycobacterium aurum, Escherichia coli, and Staphylococcus aureus as well as a human monocyte-derived macrophage (THP-1), and murine macrophage (RAW 264.7) cell lines to assess their antibacterial and cytotoxic potential, respectively. The compounds showed activity in the range of 1.

Synthesis and taste assessment of meloxicam pivalate.

Meloxicam (MX), a nonsteroidal anti-inflammatory drug, widely used to treat arthritis, has a very bitter taste. Chemical modification of the bitter functionality was achieved by synthesis of a prodrug, meloxicam pivalate (MXP). Taste improvement was evaluated using single bottle-test rat model.

Oxadiazole scaffolds in anti-tuberculosis drug discovery.

With the increasing number of cases of latent and drug resistant tuberculosis, there is an urgent need to develop new, potent molecules capable of combating this deadly disease. Molecules containing oxadiazoles are one such class that could be considered to fulfil this need. Oxadiazole regioisomers have been explored in drug discovery programs for their ability to act as effective linkers and also as pharmacophoric features.

Evaluation of Phytopolyphenols for their gp120-CD4 Binding Inhibitory Properties by In Silico Molecular Modelling & In Vitro Cell Line Studies.

Background: Lack of effective early-stage HIV-1 inhibitor instigated the need for screening of novel gp120-CD4 binding inhibitor. Polyphenols, a secondary metabolite derived from natural sources are reported to have broad spectrum HIV-1 inhibitory activity. However, the gp120-CD4 binding inhibitory activity of polyphenols has not been analysed in silico yet.

Tetrahydrocurcumin-loaded vaginal nanomicrobicide for prophylaxis of HIV/AIDS: in silico study, formulation development, and in vitro evaluation.

A vaginal microbicide is a front-line women-dependent approach and an alternative to a condom for prevention of unprotected sexual intercourse-associated HIV. The microbicide research is still in its infancy with several products in the clinical studies being reported to have good efficacy, safe, but with poor adherence. One such molecule reported with an excellent efficacy when tested preclinically is curcumin, a natural polyphenol derived from Curcuma longa.

Molecular dynamic simulations on an inhibitor of anti-apoptotic Bcl-2 proteins for insights into its interaction mechanism for anti-cancer activity.

Inhibition of normal cellular apoptosis or programed cell death is the hallmark of all cancers. Apoptotic dysregulation can result in numerous pathological conditions, such as cancers, autoimmune disorders, and neurodegeneration. Members of the BCL-2 family of proteins regulate the process of apoptosis by its promotion or inhibition and overexpression of the pro-survival anti-apoptotic proteins (Bcl-2, Bcl-xL, and Mcl-1) has been associated with tumor maintenance, growth and progression Small molecules and peptides which bind the BH3 binding groove of these proteins have been explored in the recent times for their anticancer potential.

Rational design of coumarin derivatives as antituberculosis agents.

Aim: A series of coumarin derivatives was designed as potential antituberculosis agents.

Results: The compounds were screened against active and dormant Mycobacterium tuberculosis (Mtb). Compounds 3k and 3n were found to have the most promising activity against replicating MtbH37Rv exhibiting minimum inhibitory concentration of 4.

Homology modelling of human divalent metal transporter (DMT): Molecular docking and dynamic simulations for duodenal iron transport.

Iron transport through the duodenum is regulated by carrier proteins, one of which is the ubiquitously distributed divalent metal transporter (DMT1) which is responsible for the uptake of iron across the apical surface of the duodenal enterocyte. The crystallographic structure of Staphylococcus capitis divalent metal ion transporter (ScaDMT1) was obtained and it was used as a template for the construction of a homology model of human divalent metal transporter (hDMT1). The binding site for hDMT1 was determined by using SiteMap as well as molecular docking studies on ScaDMT1.

Design and synthesis of 5-(5-nitrothiophen-2-yl)-3-phenyl-4,5-dihydro-1H-pyrazole derivatives with improved solubility and potential antituberculosis activity.

We report the design-synthesis of several nitrothiophene containing molecules as antituberculosis agents. The molecules were designed on the basis of previously reported nitrofuran molecules in our laboratory, and the α,β-unsaturated linker was modified to cyclized linker in order to overcome the challenge of low solubility and possible toxicity. The stereo-electronic properties such as HOMO, LUMO, and HOMO-LUMO gap along with other properties such as aqueous solvation energies and QPLogS values were studied.