Development and validation of HPLC-UV and LC-MS/MS methods for the quantitative determination of a novel aminothiazole in preclinical samples.

Aminothiazoles are the important class of chemical groups which have proven their broad range of biological activities. A novel aminothiazole (21MAT) was quantified in analytical solutions using a high-performance liquid chromatography (HPLC) approach that was developed and partially validated for the analysis of in vitro experimental samples. An isocratic elution on reverse phase Phenomenex Luna C (50 mm × 4.

A phenylpropanoid dimer from the leaves of .

Phytochemical analyses of the chloroform extract of L. var. , Piperaceae, leaves led to the isolation of a new phenylpropanoid analogue for the first time: hydroxychavicol dimer, 2-('-hydroxychavicol)-hydroxychavicol (), on the basis of spectroscopic data 1 D (H and C) and 2 D (H-H COSY and HMBC) NMR, as well as ESI-MS, FT-IR, HR-ESI-MS and LC-ESI-MS.

Mycobactin Analogues with Excellent Pharmacokinetic Profile Demonstrate Potent Antitubercular Specific Activity and Exceptional Efflux Pump Inhibition.

In this study, we have designed and synthesized pyrazoline analogues that partially mimic the structure of mycobactin, to address the requirement of novel therapeutics to tackle the emerging global challenge of antimicrobial resistance (AMR). Our investigation resulted in the identification of novel lead compounds and as potential mycobactin biosynthesis inhibitors against mycobacteria. Moreover, candidates efficiently eradicated intracellularly surviving mycobacteria.

A Critical Observation on the Design and Development of Reported Peptide Inhibitors of DENV NS2B-NS3 Protease in the Last Two Decades.

Dengue is one of the neglected tropical diseases, which remains a reason for concern as cases seem to rise every year. The failure of the only dengue vaccine, Dengvaxia® , has made the problem more severe and humanity has no immediate respite from this global burden. Dengue virus (DENV) NS2B-NS3 protease is an attractive target partly due to its role in polyprotein processing.

A short survey of dengue protease inhibitor development in the past 6 years (2015-2020) with an emphasis on similarities between DENV and SARS-CoV-2 proteases.

Dengue remains a disease of significant concern, responsible for nearly half of all arthropod-borne disease cases across the globe. Due to the lack of potent and targeted therapeutics, palliative treatment and the adoption of preventive measures remain the only available options. Compounding the problem further, the failure of the only dengue vaccine, Dengvaxia®, also delivered a significant blow to any hopes for the treatment of dengue fever.

The Mycobactin Biosynthesis Pathway: A Prospective Therapeutic Target in the Battle against Tuberculosis.

The alarming rise in drug-resistant clinical cases of tuberculosis (TB) has necessitated the rapid development of newer chemotherapeutic agents with novel mechanisms of action. The mycobactin biosynthesis pathway, conserved only among the mycolata family of actinobacteria, a group of intracellularly surviving bacterial pathogens that includes , generates a salicyl-capped peptide mycobactin under iron-stress conditions in host macrophages to support the iron demands of the pathogen. This essentiality makes this less explored mycobactin biosynthesis pathway a promising endogenous target for novel lead-compounds discovery.

Synthetic and Semi-synthetic Drugs as a Promising Therapeutic Option for the Treatment of COVID-19.

The novel coronavirus disease-19 (COVID-19) is a global pandemic that emerged from Wuhan, China, and has spread all around the world, affecting 216 countries or territories with 21,732,472 people infected and 770,866 deaths globally (as per WHO COVID-19 updates of August 18, 2020). Continuous efforts are being made to repurpose the existing drugs and develop vaccines for combating this infection. Despite, to date, no certified antiviral treatment or vaccine exists.

Two new anticancer phenolic derivatives from leaves of Linn.

In this study, phytochemical analyses of the chloroform extract of L. var. and , Piperaceae, leaves led to the isolation of two new phenolic derivatives: 1--decanoyl hydroxy-benzoic acid/1--decanoyl phenol () and 3-phenol () on the basis of spectroscopic data 1D NMR (H, C) and 2D NMR (H - H COSY, HMBC) as well as ESI-MS, FT-IR and HR-ESI-MS analyses.

Quinazolinone derivative BNUA-3 ameliorated [NDEA+2-AAF]-induced liver carcinogenesis in SD rats by modulating AhR-CYP1B1-Nrf2-Keap1 pathway.

Cytochrome P450 1B1, considered as one of the novel chemotherapeutic targets involved in cancer prevention and therapy is also associated with the conversion of procarcinogens into their active metabolites. The aryl hydrocarbon receptor (AhR) is responsible for mediating different biological responses to a wide variety of environmental pollutants and also causes transcriptional activation of cytochrome P450 enzymes including CYP1B1 and thus plays a pivotal role for initiating cancer and its progression. On the other hand, active carcinogenic metabolites and reactive oxygen species-mediated stress alter different molecular signalling pathways and gene expressions.

A novel druggable interprotomer pocket in the capsid of rhino- and enteroviruses.

Rhino- and enteroviruses are important human pathogens, against which no antivirals are available. The best-studied inhibitors are "capsid binders" that fit in a hydrophobic pocket of the viral capsid. Employing a new class of entero-/rhinovirus inhibitors and by means of cryo-electron microscopy (EM), followed by resistance selection and reverse genetics, we discovered a hitherto unknown druggable pocket that is formed by viral proteins VP1 and VP3 and that is conserved across entero-/rhinovirus species.

Scaffold Based Search on the Desferithiocin Archetype.

Iron overload disorder and diseases where iron mismanagement plays a crucial role require orally available iron chelators with favourable pharmacokinetic and toxicity profile. Desferrithiocin (DFT), a tridentate and orally available iron chelator has a favourable pharmacokinetic profile but its use has been clinically restricted due to its nephrotoxic potential. The chemical architecture of the DFT has been naturally well optimized for better iron chelation and iron clearance from human biological system.

CYP enzymes, expressed within live human suspension cells, are superior to widely-used microsomal enzymes in identifying potent CYP1A1/CYP1B1 inhibitors: Identification of quinazolinones as CYP1A1/CYP1B1 inhibitors that efficiently reverse B[a]P toxicity and cisplatin resistance.

Microsomal cytochrome P450 (CYP) enzymes, isolated from recombinant bacterial/insect/yeast cells, are extensively used for drug metabolism studies. However, they may not always portray how a developmental drug would behave in human cells with intact intracellular transport mechanisms. This study emphasizes the usefulness of human HEK293 kidney cells, grown in 'suspension' for expression of CYPs, in finding potent CYP1A1/CYP1B1 inhibitors, as possible anticancer agents.

Cink4T, a quinazolinone-based dual inhibitor of Cdk4 and tubulin polymerization, identified via ligand-based virtual screening, for efficient anticancer therapy.

Inhibition of cyclin dependent kinase 4 (Cdk4) prevents cancer cells from entering the early G/G phase of the cell division cycle whereas inhibiting tubulin polymerization blocks cancer cells' ability to undergo mitosis (M) late in the cell cycle. We had reported earlier that two non-planar and relatively non-toxic fascaplysin derivatives, an indole and a tryptoline, inhibit Cdk4 with IC values of 6.2 and 10 μM, respectively.

Phytoestrogens and their synthetic analogues as substrate mimic inhibitors of CYP1B1.

Phytoestrogens are class of natural compounds that shares structural similarity with estrogen and has the capacity to alter the fertilization in mammals. Till early 1990s, the natural phytoestrogens as well as their synthetic analogues were explored for their fertility modulating activity. During late 1990s, two findings renewed the interest on phytoestrogens as means to control hormone induced cancer: (i) revelation of overexpression of CYP1B1 in breast & ovarian cancer and (ii) protection offered by alphanapthoflavone (ANF) against hormone induced cancer.

The new ether derivative of phenylpropanoid and bioactivity was investigated from the leaves of L.

A new ether derivative of phenylpropanoid compound, (-isohydroxychavicol)-chavicol octanyl ether () along with one known phenylpropanoid named pyrocatechol or hydroxychavicol () were isolated from var. collected from Tumluk district, West Bengal India. We first report the presence of compound in the genus .

Crystal structures and Hirshfeld surface analyses of 2-[(4,6-di-amino-pyrimidin-2-yl)sulfan-yl]--(pyridin-2-yl)acetamide and 2-[(4,6-di-amino-pyrimidin-2-yl)sulfan-yl]--(pyrazin-2-yl)acetamide.

In the title compounds, CHNOS (I) and CHNOS (II), the di-amino-pyrimidine ring makes dihedral angles of 71.10 (9)° with the pyridine ring in (I) and 62.93 (15)° with the pyrazine ring in (II).

New chemical constituents from the Piper betle Linn. (Piperaceae).

The phytochemical investigation of chloroform extract from Piper betle var. haldia, Piperaceae, leaves has resulted in the isolation of two new chemical constituents which were identified as 1-n-dodecanyloxy resorcinol (H1) and desmethylenesqualenyl deoxy-cepharadione-A (H4), on the basis of spectroscopic data 1D NMR (H and C) and 2D NMR (H-H COSY and HMBC) as well as ESI-MS, FT-IR and HR-ESI-MS analyses. Compounds H1 and H4 showed excellent antioxidant DPPH free radical scavenging activity with IC values of 7.

Crystal structures of 2-[(4,6-di-amino-pyrimidin-2-yl)sulfan-yl]--(2,4-di-methyl-phen-yl)acetamide and 2-[(4,6-di-amino-pyrimidin-2-yl)sulfan-yl]--(3-meth-oxy-phen-yl)acetamide.

In the title compounds, CHNOS (I) and CHNOS (II), the dihedral angle between the pyrimidine and benzene rings is 58.64 (8)° in (I) and 78.33 (9)° in (II).

Crystal structures of -(4-chloro-phen-yl)-2-[(4,6-di-amino-pyrimidin-2-yl)sulfan-yl]acetamide and -(3-chloro-phen-yl)-2-[(4,6-di-amino-pyrimidin-2-yl)sulfan-yl]acetamide.

The title compounds, CHClNOS, (I), and CHClNOS, (II), are 2-[(di-amino-pyrimidin-2-yl)sulfan-yl]acetamides. Compound (II), crystallizes with two independent mol-ecules ( and ) in the asymmetric unit. In each of the mol-ecules, in both (I) and (II), an intra-molecular N-H⋯N hydrogen bond forms an (7) ring motif.

Computer-Aided Structure Based Drug Design Approaches for the Discovery of New Anti-CHIKV Agents.

Background: Chikungunya is a viral infection caused by Chikungunya virus (CHIKV), an arbovirus transmitted through mosquito (Aedes aegypti and Aedes albopictus) bite. The virus from sylvatic cycle in Africa mutated to new vector adaptation and became one of the major emerging and re-emerging viral infections in the past decade, affecting more than 40 countries. Efforts are being made by many researches to develop means to prevent and control the infection through vaccines and vector control strategy.

Bioactive phenylpropanoid analogues from Piper betle L. var. birkoli leaves.

Phytochemical analyses of the chloroform extract of Piper betle L. var. birkoli, Piperaceae, leaves led to the isolation of two new phenylpropanoid analogues: bis-chavicol dodecanoyl ester (2) and bis-hydroxychavicol dodecanoyl ester (3), along with one known compound: allyl-3-methoxy-4-hydroxybenzene (1) on the basis of spectroscopic data 1D (H and C) and 2D (H-H COSY and HMBC) NMR, as well as ESI-MS, FT-IR, HR-ESI-MS and LC-ESI-MS.

Quinazoline derivatives as selective CYP1B1 inhibitors.

CYP1B1 is implicated to have a role in the development of breast, ovarian, renal, skin and lung carcinomas. It has been suggested that identification of potent and specific CYP1B1 inhibitors can lead to a novel treatment of cancer. Flavonoids have a compact rigid skeleton which fit precisely within the binding cavity of CYP1B1.

Crystal structures of 2-[(4,6-di-amino-pyrimidin-2-yl)sulfan-yl]--(naphthalen-1-yl)acetamide and 2-[(4,6-di-amino-pyrimidin-2-yl)sulfan-yl]--(4-fluoro-phen-yl)acetamide.

The title compounds, CHNOS, (I), and CHFNOS, (II), are [(di-amino-pyrimidine)-sulfan-yl]acetamide derivatives. In (I), the pyrimidine ring is inclined to the naphthalene ring system by 55.5 (1)°, while in (II), the pyrimidine ring is inclined to the benzene ring by 58.

Biphenyl urea derivatives as selective CYP1B1 inhibitors.

Highly selective CYP1B1 inhibitors have potential in the treatment of hormone-induced breast and prostate cancers. Mimicry of potent and selective CYP1B1 inhibitors, α-naphthoflavone and stilbenes, revealed that two sets of hydrophobic clusters suitably linked via a polar linker could be implanted into a new scaffold 'biphenyl ureas' to create potentially a new class of CYP1B1 inhibitors. A series of sixteen biphenyl ureas were synthesized and screened for CYP1B1 and CYP1A1 inhibition in Sacchrosomes™, yeast-derived recombinant microsomal enzymes.