ABSTRACT
The crystallographic structure of the FolB enzyme from Mycobacterium tuberculosis (MtFolB), complexed with its inhibitor 8-mercaptoguanine (8-MG), was elucidated at a resolution of 1.95 Å. A novel series of S8-functionalized 8-MG derivatives were synthesised and evaluated as in vitro inhibitors of dihydroneopterin aldolase (DHNA, EC 4.1.2.25) activity of MtFolB. These compounds exhibited IC50 values in the submicromolar range. Evaluation of the activity for five compounds indicated their inhibition mode and inhibition constants. Molecular docking analyses were performed to determine the enzyme-inhibitor intermolecular interactions and ligand conformations upon complex formation. The inhibitory activities of all compounds against the M. tuberculosis H37Rv strain were evaluated. Compound 3e exhibited a minimum inhibitory concentration in the micromolar range. Finally, Compound 3e showed no apparent toxicity in both HepG2 and Vero cells. The findings presented herein will advance the quest for novel, specific inhibitors targeting MtFolB, an attractive molecular target for TB drug development.
Subject(s)
Aldehyde-Lyases , Antitubercular Agents , Dose-Response Relationship, Drug , Enzyme Inhibitors , Microbial Sensitivity Tests , Mycobacterium tuberculosis , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/enzymology , Antitubercular Agents/pharmacology , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Structure-Activity Relationship , Aldehyde-Lyases/antagonists & inhibitors , Aldehyde-Lyases/metabolism , Aldehyde-Lyases/chemistry , Vero Cells , Molecular Structure , Crystallography, X-Ray , Chlorocebus aethiops , Animals , Guanine/pharmacology , Guanine/chemistry , Guanine/analogs & derivatives , Guanine/chemical synthesis , Molecular Docking Simulation , Hep G2 Cells , Models, MolecularABSTRACT
Tuberculosis remains a global health problem that affects millions of people around the world. Despite recent efforts in drug development, new alternatives are required. Herein, a series of 27 N-(4-(benzyloxy)benzyl)-4-aminoquinolines were synthesized and evaluated for their ability to inhibit the M. tuberculosis H37Rv strain. Two of these compounds exhibited minimal inhibitory concentrations (MICs) similar to the first-line drug isoniazid. In addition, these hit compounds were selective for the bacillus with no significant change in viability of Vero and HepG2 cells. Finally, chemical stability, permeability and metabolic stability were also evaluated. The obtained data show that the molecular hits can be optimized aiming at the development of drug candidates for tuberculosis treatment.
Subject(s)
Mycobacterium tuberculosis , Tuberculosis , Aminoquinolines/pharmacology , Antitubercular Agents/chemistry , Humans , Isoniazid/pharmacology , Microbial Sensitivity Tests , Tuberculosis/drug therapyABSTRACT
Leishmaniasis still stands as one of the most prevalent neglected tropical diseases in the least developed and emerging countries. The recommended therapeutic arsenal to treat leishmaniasis is characterized by several shortcomings, and resistance has already been reported. Hence, this dramatic background highlights the pressing need to develop novel, affordable, and safe antileishmanial drugs. Multiple classes of natural compounds have been reported to possess antileishmanial activity. Among these classes, iridoids stand out as a special type of monoterpenoids with diverse biological properties-including their antileishmanial potential. This review aims to discuss the available literature between 1991 and 2020 related to the antileishmanial activity of the iridoid class. Throughout the past decades, various investigations attributed antileishmanial action to assorted iridoid types, including inhibitory potential towards validated drug targets and immunomodulatory activity. The latter deserves special attention due to the ability of some iridoids to improve the host's immune response against parasites. It opens the possibility of iridoids become adjuncts in leishmaniasis treatments by improving the efficacy of currently employed drugs. Furthermore, the present study intends to provide a convenient visual representation of which iridoids and Leishmania spp. species have been most investigated as a guide for further researches.