Potentiating metronidazole scaffold against resistant Trichomonas: Design, synthesis, biology and 3D-QSAR analysis

Lalit Kumar, Ashish Jain, Nand Lal, Amit Sarswat, Santosh Jangir, Lokesh Kumar, Vishal Singh, Priyanka Shah, Swatantra K. Jain, Jagdamba P. Maikhuri, Mohammad I. Siddiqi, Gopal Gupta, Vishnu L. Sharma

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)83-87
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume3
Issue number2
DOIs
StatePublished - Feb 9 2012

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Trichomonas
Quantitative Structure-Activity Relationship
Metronidazole
Scaffolds (biology)
Trichomonas vaginalis
Drug Resistance
Spermatozoa
Pharmaceutical Preparations
Ethane
Lactobacillus
Contraceptive Agents
HeLa Cells
Safety

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Cite this

Kumar, Lalit ; Jain, Ashish ; Lal, Nand ; Sarswat, Amit ; Jangir, Santosh ; Kumar, Lokesh ; Singh, Vishal ; Shah, Priyanka ; Jain, Swatantra K. ; Maikhuri, Jagdamba P. ; Siddiqi, Mohammad I. ; Gupta, Gopal ; Sharma, Vishnu L. / Potentiating metronidazole scaffold against resistant Trichomonas : Design, synthesis, biology and 3D-QSAR analysis. In: ACS Medicinal Chemistry Letters. 2012 ; Vol. 3, No. 2. pp. 83-87.
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abstract = "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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Kumar, L, Jain, A, Lal, N, Sarswat, A, Jangir, S, Kumar, L, Singh, V, Shah, P, Jain, SK, Maikhuri, JP, Siddiqi, MI, Gupta, G & Sharma, VL 2012, 'Potentiating metronidazole scaffold against resistant Trichomonas: Design, synthesis, biology and 3D-QSAR analysis', ACS Medicinal Chemistry Letters, vol. 3, no. 2, pp. 83-87. https://doi.org/10.1021/ml200161t

Potentiating metronidazole scaffold against resistant Trichomonas : Design, synthesis, biology and 3D-QSAR analysis. / Kumar, Lalit; Jain, Ashish; Lal, Nand; Sarswat, Amit; Jangir, Santosh; Kumar, Lokesh; Singh, Vishal; Shah, Priyanka; Jain, Swatantra K.; Maikhuri, Jagdamba P.; Siddiqi, Mohammad I.; Gupta, Gopal; Sharma, Vishnu L.

In: ACS Medicinal Chemistry Letters, Vol. 3, No. 2, 09.02.2012, p. 83-87.

Research output: Contribution to journalArticle

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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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