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1.
Anal Methods ; 15(23): 2853-2860, 2023 06 15.
Article in English | MEDLINE | ID: mdl-37260380

ABSTRACT

Discovery of the biological signaling roles of H2S has spurred great interest in developing reliable methods for its accurate detection and quantification. As considerable variation in its levels is seen during pathological conditions such as sepsis, real-time quantification methods have relevance in diagnosis as well. Of various approaches, reaction-based probes which respond through 'off-on' fluorescence emission remain the most studied. Since the intensity of emission is related to the analyte concentration in these measurements, the presence of built-in features which provide an opportunity for internal referencing will be advantageous. In view of this, a dual mode response system that senses H2S through characteristic fluorescence and Raman (SERS) signals based on a 1H-pyrrol-3(2H)-one scaffold was developed and is the main highlight of this report. This probe offers several advantages such as fast response (<1 min), and high selectivity and sensitivity with a detection limit of ∼7 nM. Imaging of H2S in HepG2 cells, making use of the SERS signal from the thiolysis product is also demonstrated.


Subject(s)
Fluorescent Dyes , Hydrogen Sulfide , Fluorescence
2.
ChemMedChem ; 18(16): e202300081, 2023 08 15.
Article in English | MEDLINE | ID: mdl-37256820

ABSTRACT

Pharmacophore hybridization is an attractive strategy to identify new leads against multifactorial diseases such as cancer. Based on literature analysis of compounds possessing 'vicinal diaryl' fragment in their structure, we considered Discoipyrroles A-D and Combretastatin A-4 (CA-4) as possible components in hybrid design. Discoipyrrole C (Dis C) and CA-4 were used as reference compounds in these studies and their hybrids, in the form of 4,5-diaryl-1H-pyrrol-3(2H)-ones, were synthesized from suitable amino acid precursors though their ynone intermediates. Of these, the hybrid having exact substitution pattern as that of CA-4 showed better potency and selectivity than Dis C, but its activity was less compared to CA-4. This new analog disrupted interphase microtubules by inhibiting tubulin assembly by binding to the colchicine site, induced multipolar spindles, caused cell cycle block and apoptosis in HeLa cells. It also inhibited colony formation and migration of breast cancer cell lines.


Subject(s)
Antineoplastic Agents , Tubulin , Humans , Models, Molecular , HeLa Cells , Cell Proliferation , Tubulin/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Tubulin Modulators/pharmacology , Tubulin Modulators/chemistry , Cell Line, Tumor , Structure-Activity Relationship , Molecular Structure
3.
ChemMedChem ; 17(2): e202100472, 2022 01 19.
Article in English | MEDLINE | ID: mdl-34717044

ABSTRACT

Although many quinolones have shown promise as potent antimalarials, their clinical development has been slow due to poor performance in vivo. Insights into structural modifications that can improve their therapeutic potential will be very valuable in this vibrant area of research. Our studies involving a library of quinolones which vary in substitution pattern at N1, C3, C6 and C7 positions have shown that the presence of adenine moiety at C7 can bring a noticeable improvement in activity compared to other heterocyclic groups at this location. The most potent compound emerged from this study showed IC50 values of 0.38 µM and 0.75 µM against chloroquine-sensitive and -resistant (W2) strains, respectively. Docking analysis in the Qo site of cytochrome bc1 complex revealed the contribution of a key H-bonding interaction from the adenine unit in target binding. This corroborates with compound-induced loss of mitochondrial functions. These findings not only open avenues for further exploration of antimalarial potential of adenine-modified quinolones, but also suggests broader opportunities during lead-optimization against other antimalarial targets.


Subject(s)
Adenine/pharmacology , Antimalarials/pharmacology , Malaria, Falciparum/drug therapy , Plasmodium falciparum/drug effects , Quinolones/pharmacology , Adenine/chemistry , Animals , Antimalarials/chemical synthesis , Antimalarials/chemistry , Chlorocebus aethiops , Dose-Response Relationship, Drug , Molecular Structure , Parasitic Sensitivity Tests , Quinolones/chemical synthesis , Quinolones/chemistry , Structure-Activity Relationship , Vero Cells
4.
Bioorg Med Chem Lett ; 30(22): 127594, 2020 11 15.
Article in English | MEDLINE | ID: mdl-33010449

ABSTRACT

New cisplatin analogs in which the diamminedichloro-Pt(II) unit is conjugated to dihydroquinoline- or tetrahydroquinoline frameworks were synthesized and subjected to biological evaluation in order to understand their effects on cellular redox homeostasis and cell viability. They exhibited better selectivity towards cancer cells (A549) compared to mice fibroblast NIH3T3 cells, with cytotoxicity in the same range as that of cisplatin. There was structure-dependent variation in the levels of ROS and were also able to induce cell death, as evidenced by accumulation of cells in sub-G1 phase.


Subject(s)
Antineoplastic Agents/pharmacology , Cisplatin/pharmacology , Heterocyclic Compounds/pharmacology , Quinolines/pharmacology , A549 Cells , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Cisplatin/chemical synthesis , Cisplatin/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Humans , Mice , Molecular Structure , NIH 3T3 Cells , Oxidation-Reduction , Quinolines/chemistry , Structure-Activity Relationship
6.
Chem Commun (Camb) ; 53(32): 4485-4488, 2017 Apr 18.
Article in English | MEDLINE | ID: mdl-28382364

ABSTRACT

A simple replacement of a H atom by Br transformed non-gelating aryl triazolyl amino acid benzyl ester into a versatile gelator, which formed shape-persistent, self-healing and mouldable gels. The 'bromo-aryl benzyl ester' fragment was then transplanted into another framework, which resulted in similar solvent preference and gelation efficiency.

7.
Eur J Med Chem ; 123: 557-567, 2016 Nov 10.
Article in English | MEDLINE | ID: mdl-27517804

ABSTRACT

The dual effect of FtsZ inhibition and oxidative stress by a group of 1,2-dihydroquinolines that culminate in bactericidal effect on mycobacterium strains is demonstrated. They inhibited the non-pathogenic Mycobacterium smegmatis mc(2) 155 with MIC as low as 0.9 µg/mL and induced filamentation. Detailed studies revealed their ability to inhibit polymerization and GTPase activity of MtbFtsZ (Mycobacterial filamentous temperature sensitive Z) with an IC50 value of ∼40 µM. In addition to such target specific effects, these compounds exerted a global cellular effect by causing redox-imbalance that was evident from overproduction of ROS in treated cells. Such multi-targeting effect with one chemical scaffold has considerable significance in this era of emerging drug resistance and could offer promise in the development of new therapeutic agents against tuberculosis.


Subject(s)
Bacterial Proteins/antagonists & inhibitors , Mycobacterium smegmatis/drug effects , Mycobacterium smegmatis/metabolism , Quinones/chemistry , Quinones/pharmacology , Bacillus subtilis/drug effects , GTP Phosphohydrolases/chemistry , Microbial Sensitivity Tests , Oxidation-Reduction/drug effects , Protein Multimerization/drug effects , Protein Structure, Quaternary , Reactive Oxygen Species/metabolism
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