Design, synthesis, and pharmacological evaluation of mefloquine-based ligands as novel antituberculosis agents

Jialin Mao, Yuehong Wang, Baojie Wan, Alan P. Kozikowski, Scott G. Franzblau

Research output: Contribution to journalArticle

Abstract

Tuberculosis (TB) is presently regarded as one of the most dangerous infective diseases worldwide and one of the major AIDS-associated infections. To shorten the current treatment regimen, there is an urgent need to identify new anti-TB agents which are active against both replicating TB (R-TB) and nonreplicating TB (NRP-TB). Mefloquine, a well-known antimalarial drug was found to possess reasonable activity against NRP-TB, and accordingly, 30 new analogues were synthesized and evaluated for their anti-TB activity against Mycobacterium tuberculosis H37Rv. As the target of mefloquine in Mycobacterium tuberculosis remains unknown, we resorted to modifying mefloquine in a variety of chemically convenient ways, which led us in turn to the active hydrazone 10a. Further modifications of 10a led to compound 7 f, with an improved anti-TB activity/selectivity profile with both less cytotoxicity and less predicted CNS side effects compared with mefloquine. The clear structure-activity relationships (SARs) derived from this study should facilitate our ultimate goal of identifying improved anti-TB agents.

Original languageEnglish (US)
Pages (from-to)1624-1630
Number of pages7
JournalChemMedChem
Volume2
Issue number11
DOIs
StatePublished - Nov 12 2007
Externally publishedYes

Fingerprint

Mefloquine
Tuberculosis
Pharmacology
Ligands
Hydrazones
Mycobacterium tuberculosis
Antimalarials
Cytotoxicity
Structure-Activity Relationship
Acquired Immunodeficiency Syndrome
Infection

Keywords

  • Hydrazones
  • Ligand-based drug design
  • Mefloquine
  • Structure-activity relationships
  • Tuberculosis

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

Cite this

Design, synthesis, and pharmacological evaluation of mefloquine-based ligands as novel antituberculosis agents. / Mao, Jialin; Wang, Yuehong; Wan, Baojie; Kozikowski, Alan P.; Franzblau, Scott G.

In: ChemMedChem, Vol. 2, No. 11, 12.11.2007, p. 1624-1630.

Research output: Contribution to journalArticle

Mao, Jialin ; Wang, Yuehong ; Wan, Baojie ; Kozikowski, Alan P. ; Franzblau, Scott G. / Design, synthesis, and pharmacological evaluation of mefloquine-based ligands as novel antituberculosis agents. In: ChemMedChem. 2007 ; Vol. 2, No. 11. pp. 1624-1630.
@article{643377377cb743a8b0e501b8545ba788,
title = "Design, synthesis, and pharmacological evaluation of mefloquine-based ligands as novel antituberculosis agents",
abstract = "Tuberculosis (TB) is presently regarded as one of the most dangerous infective diseases worldwide and one of the major AIDS-associated infections. To shorten the current treatment regimen, there is an urgent need to identify new anti-TB agents which are active against both replicating TB (R-TB) and nonreplicating TB (NRP-TB). Mefloquine, a well-known antimalarial drug was found to possess reasonable activity against NRP-TB, and accordingly, 30 new analogues were synthesized and evaluated for their anti-TB activity against Mycobacterium tuberculosis H37Rv. As the target of mefloquine in Mycobacterium tuberculosis remains unknown, we resorted to modifying mefloquine in a variety of chemically convenient ways, which led us in turn to the active hydrazone 10a. Further modifications of 10a led to compound 7 f, with an improved anti-TB activity/selectivity profile with both less cytotoxicity and less predicted CNS side effects compared with mefloquine. The clear structure-activity relationships (SARs) derived from this study should facilitate our ultimate goal of identifying improved anti-TB agents.",
keywords = "Hydrazones, Ligand-based drug design, Mefloquine, Structure-activity relationships, Tuberculosis",
author = "Jialin Mao and Yuehong Wang and Baojie Wan and Kozikowski, {Alan P.} and Franzblau, {Scott G.}",
year = "2007",
month = "11",
day = "12",
doi = "10.1002/cmdc.200700112",
language = "English (US)",
volume = "2",
pages = "1624--1630",
journal = "ChemMedChem",
issn = "1860-7179",
publisher = "John Wiley and Sons Ltd",
number = "11",

}

TY - JOUR

T1 - Design, synthesis, and pharmacological evaluation of mefloquine-based ligands as novel antituberculosis agents

AU - Mao, Jialin

AU - Wang, Yuehong

AU - Wan, Baojie

AU - Kozikowski, Alan P.

AU - Franzblau, Scott G.

PY - 2007/11/12

Y1 - 2007/11/12

N2 - Tuberculosis (TB) is presently regarded as one of the most dangerous infective diseases worldwide and one of the major AIDS-associated infections. To shorten the current treatment regimen, there is an urgent need to identify new anti-TB agents which are active against both replicating TB (R-TB) and nonreplicating TB (NRP-TB). Mefloquine, a well-known antimalarial drug was found to possess reasonable activity against NRP-TB, and accordingly, 30 new analogues were synthesized and evaluated for their anti-TB activity against Mycobacterium tuberculosis H37Rv. As the target of mefloquine in Mycobacterium tuberculosis remains unknown, we resorted to modifying mefloquine in a variety of chemically convenient ways, which led us in turn to the active hydrazone 10a. Further modifications of 10a led to compound 7 f, with an improved anti-TB activity/selectivity profile with both less cytotoxicity and less predicted CNS side effects compared with mefloquine. The clear structure-activity relationships (SARs) derived from this study should facilitate our ultimate goal of identifying improved anti-TB agents.

AB - Tuberculosis (TB) is presently regarded as one of the most dangerous infective diseases worldwide and one of the major AIDS-associated infections. To shorten the current treatment regimen, there is an urgent need to identify new anti-TB agents which are active against both replicating TB (R-TB) and nonreplicating TB (NRP-TB). Mefloquine, a well-known antimalarial drug was found to possess reasonable activity against NRP-TB, and accordingly, 30 new analogues were synthesized and evaluated for their anti-TB activity against Mycobacterium tuberculosis H37Rv. As the target of mefloquine in Mycobacterium tuberculosis remains unknown, we resorted to modifying mefloquine in a variety of chemically convenient ways, which led us in turn to the active hydrazone 10a. Further modifications of 10a led to compound 7 f, with an improved anti-TB activity/selectivity profile with both less cytotoxicity and less predicted CNS side effects compared with mefloquine. The clear structure-activity relationships (SARs) derived from this study should facilitate our ultimate goal of identifying improved anti-TB agents.

KW - Hydrazones

KW - Ligand-based drug design

KW - Mefloquine

KW - Structure-activity relationships

KW - Tuberculosis

UR - http://www.scopus.com/inward/record.url?scp=49649095678&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=49649095678&partnerID=8YFLogxK

U2 - 10.1002/cmdc.200700112

DO - 10.1002/cmdc.200700112

M3 - Article

C2 - 17680579

AN - SCOPUS:49649095678

VL - 2

SP - 1624

EP - 1630

JO - ChemMedChem

JF - ChemMedChem

SN - 1860-7179

IS - 11

ER -