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1.
SAR QSAR Environ Res ; 33(2): 89-109, 2022 Feb.
Article in English | MEDLINE | ID: mdl-35102805

ABSTRACT

Multidrug-resistant tuberculosis (MDR-TB) is a severe threat to mankind because most drugs are ineffective in inhibiting tubercular strains. Due to the increase of MDR-TB, many first and second-line drugs are ineffective against tubercular strains. To combat the resistance of currently accessible drugs, structural changes must be made on a regular basis. Thus, in the search for new antimycobacterial drugs, a series of 1-(2-(1H-indol-3-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)-3-phenylprop-2-en-1-ones (5a-o) have been developed, synthesized, characterized, and screened for antimycobacterial activity. The synthetic approach includes imine generation and cyclization using both conventional and microwave methods to create hybrid molecules with indole and oxadiazole motifs. The set of synthesized compounds have demonstrated some promising activity against tubercular strains of Mycobacterium tuberculosis (ATCC 25177) and M. bovis (ATCC 35734). Compound 5l inhibited M. bovis strain 100% in 10 µg/mL concentration, while compound 5m inhibited M. tuberculosis strain 90.4% in 30 µg/mL concentration. Molecular docking study against mycobacterial enoyl reductase (InhA) could provide well-clustered solutions to the binding modes and affinity for these molecules as compound 5l showed glide score of -12.275 and glide energy of -54.937 kcal/mol.


Subject(s)
Antitubercular Agents , Mycobacterium tuberculosis , Antitubercular Agents/pharmacology , Chemistry Techniques, Synthetic , Indoles/pharmacology , Microbial Sensitivity Tests , Microwaves , Molecular Docking Simulation , Oxadiazoles/pharmacology , Quantitative Structure-Activity Relationship , Structure-Activity Relationship
2.
Bioorg Med Chem Lett ; 26(9): 2224-8, 2016 May 01.
Article in English | MEDLINE | ID: mdl-27017114

ABSTRACT

The persistence of Mycobacterium tuberculosis (MTB) in dormant stage assists the pathogen to develop resistance against current antimycobactrial drugs. To address this issue, we report herein the synthesis of N-(4-oxo-2 substituted thiazolidin-3 yl) pyrazine-2-carbohydrazide derivatives designed by following the molecular hybridization approach using pyrazine and thiazolidenone scaffolds. The compounds were evaluated against MTB H37Ra and Mycobacterium bovis BCG in dormancy model. Most of the compounds had IC50 values in 0.3-1 µg/ml range. The active compounds were further tested for anti-proliferative activity against THP-1, Panc-1, A549, and MCF-7 cell lines using MTT assay and exhibited no significant cytotoxicity. We also report molecular docking studies using active analogs and MTB - Decaprenylphosphoryl-ß-d-ribose-2'-epimerase (DprE1) to rationalize the biological activity and to provide an insight into the probable mechanism of action and binding mode of hybridized structures. The results obtained validate the use of molecular hybridization approach and also suggest that reported compounds can provide a novel pharmacophore to synthesize lead compounds against dormat MTB.


Subject(s)
Antitubercular Agents/chemical synthesis , Pyrazines/chemistry , Thiazolidines/chemistry , Antitubercular Agents/chemistry , Molecular Docking Simulation
3.
J Biomol Struct Dyn ; 34(3): 529-39, 2016.
Article in English | MEDLINE | ID: mdl-26046587

ABSTRACT

All-atom molecular dynamics is used to investigate the transport of Na(+) across a 1,2-dioleoyl-sn-glycero-3-phosphocholine lipid bilayer facilitated by a diazacrown hydraphile. Specifically, the free energy of Na(+) passing through the bilayer is calculated using the adaptive biasing force method to study the free energy associated with the increase in Na(+) transport in the presence of the hydraphile molecule. The results show that water interaction greatly influences Na(+) transport through the lipid bilayer as water is pulled through the bilayer with Na(+) forming a water channel. The hydraphile causes a reduction in the free energy barrier for the transport of Na(+) through the head group part of the lipid bilayer since it complexes the Na(+) reducing the necessity for water to be complexed and, therefore, dragged through with Na(+), an energetically unfavorable process. The free energy associated with Na(+) being desolvated within the bilayer is significantly decreased in the presence of the hydraphile molecule; the hydraphile increases the number of solvation states of Na(+) that can be adopted, and this increase in the number of available configurations provides an entropic explanation for the success of the hydraphile.


Subject(s)
Lipid Bilayers/chemistry , Molecular Dynamics Simulation , Sodium Channels/chemistry , Hydrophobic and Hydrophilic Interactions , Ions/chemistry , Molecular Conformation , Quantum Theory , Sodium/chemistry , Solvents/chemistry , Water/chemistry
4.
Bioorg Med Chem Lett ; 22(1): 666-78, 2012 Jan 01.
Article in English | MEDLINE | ID: mdl-22104148

ABSTRACT

As a part of our ongoing research to develop novel antitubercular agents, a series of N-phenyl-3-(4-fluorophenyl)-4-substituted pyrazoles have been synthesized and tested for antimycobacterial activity in vitro against Mycobacterium tuberculosis H37Rv strain using the BACTEC 460 radiometric system. A 3D-QSAR study based on CoMFA and CoMSIA was performed on these pyrazole derivatives to correlate their chemical structures with the observed activity against M. tuberculosis. The CoMFA model provided a significant correlation of steric and electrostatic fields with the biological activity while the CoMSIA model could additionally shed light on the role of hydrogen bonding and hydrophobic features. The important features identified in the 3D-QSAR models have been used to propose new molecules whose activities are predicted higher than the existing systems. This study provides valuable directions to our ongoing endeavor of rationally designing more potent antitubercular agents.


Subject(s)
Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/metabolism , Pyrazoles/chemistry , Pyrazoles/pharmacology , Quantitative Structure-Activity Relationship , Anti-Bacterial Agents/pharmacology , Chemistry, Pharmaceutical/methods , Drug Design , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Ketones , Models, Chemical , Molecular Conformation , Static Electricity , Temperature
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