TY - JOUR
T1 - Potentiating metronidazole scaffold against resistant Trichomonas
T2 - Design, synthesis, biology and 3D-QSAR analysis
AU - Kumar, Lalit
AU - Jain, Ashish
AU - Lal, Nand
AU - Sarswat, Amit
AU - Jangir, Santosh
AU - Kumar, Lokesh
AU - Singh, Vishal
AU - Shah, Priyanka
AU - Jain, Swatantra K.
AU - Maikhuri, Jagdamba P.
AU - Siddiqi, Mohammad I.
AU - Gupta, Gopal
AU - Sharma, Vishnu L.
PY - 2012/2/9
Y1 - 2012/2/9
N2 - Metronidazole (MTZ), the FDA-approved drug against Trichomonas vaginalis (TV), is being challenged seriously by drug resistance, while its inertness to sperm makes it ineffective as a vaginal contraceptive. Thirteen piperidine dithiocarbamate hybrids of 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethane (8-20) were designed to potentiate the MTZ framework against drug resistance and sperm. New compounds were 1.2-12.1 times more effective against MTZ-susceptible and -resistant strains of TV. All of the compounds exhibited high safety toward cervical (HeLa) cells and Lactobacillus. Thirty-eight compounds were scrutinized by CoMFA and CoMSIA techniques of 3D quantitative structure-activity relationship. Good predictive r pred 2 values for CoMFA and CoMSIA models reflected the robustness of the predictive ability. This was validated by designing five new analogues (46-50), which were potently microbicidal (3-10 and 10-20 times against MTZ-susceptible and -resistant TV, respectively) and spermicidal. This in vitro study may have significant clinical relevance, which could become evident in due course.
AB - Metronidazole (MTZ), the FDA-approved drug against Trichomonas vaginalis (TV), is being challenged seriously by drug resistance, while its inertness to sperm makes it ineffective as a vaginal contraceptive. Thirteen piperidine dithiocarbamate hybrids of 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethane (8-20) were designed to potentiate the MTZ framework against drug resistance and sperm. New compounds were 1.2-12.1 times more effective against MTZ-susceptible and -resistant strains of TV. All of the compounds exhibited high safety toward cervical (HeLa) cells and Lactobacillus. Thirty-eight compounds were scrutinized by CoMFA and CoMSIA techniques of 3D quantitative structure-activity relationship. Good predictive r pred 2 values for CoMFA and CoMSIA models reflected the robustness of the predictive ability. This was validated by designing five new analogues (46-50), which were potently microbicidal (3-10 and 10-20 times against MTZ-susceptible and -resistant TV, respectively) and spermicidal. This in vitro study may have significant clinical relevance, which could become evident in due course.
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U2 - 10.1021/ml200161t
DO - 10.1021/ml200161t
M3 - Article
AN - SCOPUS:84856850369
SN - 1948-5875
VL - 3
SP - 83
EP - 87
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 2
ER -