Discovery of substituted isoxazolecarbaldehydes as potent spermicides, acrosin inhibitors and mild anti-fungal agents

Gupta, Gopal; Jain, Rajeev; Maikhuri, Jagdamba P.; Shukla, Praveen Kumar; Kumar, Manish; Roy, Amrendra Kumar; Patra, Arundhati; Singh, Vishal; Batra, Sanjay

doi:10.1093/humrep/dei041

Cited by 30 publications

(17 citation statements)

References 49 publications

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“…The minimum effective (spermicidal) concentration (MEC) was determined by the modified Sander-Cramer assay as detailed earlier (12,15). Briefly, the test compounds were dissolved in a minimum volume of DMSO and diluted with physiological saline (0.85% NaCl in distilled water) to make a 10.0 mM solution and serially diluted to 0.125 mM with saline.…”

Section: Chemicalsmentioning

confidence: 99%

“…Hence, there is a need for designed synthesis of potent, more specifically acting spermicidal microbicides for prophylactic contraception. Our enduring attempts to target human sperm through differently guided molecules against various functional moieties yielded some very promising structures (7,12,(14)(15)(16)(17)(18)(19)(20)22), but the two most promising spermicides (14,16) were weakly microbicidal against Trichomonas vaginalis (15).…”

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confidence: 99%

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Novel Trichomonacidal Spermicides

Jain

Lal

Kumar

et al. 2011

Antimicrob Agents Chemother

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Metronidazole, the U.S. Food and Drug Administration-approved drug against trichomoniasis, is nonspermicidal and thus cannot offer pregnancy protection when used vaginally. Furthermore, increasing resistance of Trichomonas vaginalis to 5-nitro-imidazoles is a cause for serious concern. On the other hand, the vaginal spermicide nonoxynol-9 (N-9) does not protect against sexually transmitted diseases and HIV in clinical situations but may in fact increase their incidence due to its nonspecific, surfactant action. We therefore designed dually active, nonsurfactant molecules that were capable of killing Trichomonas vaginalis (both metronidazole-susceptible and -resistant strains) and irreversibly inactivating 100% human sperm at doses that were noncytotoxic to human cervical epithelial (HeLa) cells and vaginal microflora (lactobacilli) in vitro. Anaerobic energy metabolism, cell motility, and defense against reactive oxygen species, which are key to survival of both sperm and Trichomonas in the host after intravaginal inoculation, depend crucially on availability of free thiols. Consequently, molecules were designed with carbodithioic acid moiety as the major pharmacophore, and chemical variations were incorporated to provide high excess of reactive thiols for interacting with accessible thiols on sperm and Trichomonas. We report here the in vitro activities, structureactivity relationships, and safety profiles of these spermicidal antitrichomonas agents, the most promising of which was more effective than N-9 (the OTC spermicide) in inactivating human sperm and more efficacious than metronidazole in killing Trichomonas vaginalis (including metronidazole-resistant strain). It also significantly reduced the available free thiols on human sperm and inhibited the cytoadherence of Trichomonas on HeLa cells. Experimentally in vitro, the new compounds appeared to be safer than N-9 for vaginal use.

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Section: Chemicalsmentioning

confidence: 99%

mentioning

confidence: 99%

Novel Trichomonacidal Spermicides

Jain

Lal

Kumar

et al. 2011

Antimicrob Agents Chemother

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“…The aim of this present work focuses on the synthesis of N-heterocyclic compounds, namely the synthesis of substituted isoxazole and triazole derivatives, since an important number of compounds containing the isoxazole and the triazole scaffold are known to exhibit a variety of biological activities in the pharmaceutical [16] and medicinal areas [17]. Representative examples of synthetic drugs incorporating these motifs are Tazobactam I [18][19][20][21][22], Rufinamide II [23][24][25], phenylisoxazole derivatives III [26,27], and Bextra (Valdecoxib) IV [28][29][30].…”

Section: Introductionmentioning

confidence: 99%

“…Tazobactam I [18][19][20][21][22], Rufinamide II [23][24][25], phenylisoxazole derivatives III [26,27], and Bextra (Valdecoxib) IV [28][29][30].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Isoxazole and 1,2,3-Triazole Isoindole Derivatives via Silver- and Copper-Catalyzed 1,3-Dipolar Cycloaddition Reaction

et al. 2016

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Abstract:The CuI-or Ag 2 CO 3 -catalyzed [3+2] cycloaddition of propargyl-substituted dihydroisoindolin-1-one (3) with arylnitrile oxides 1a-d (Ar = Ph, p-MeC 6 H 4 , p-MeOC 6 H 4 , p-ClC 6 H 4 ) produces in good yields novel 3,5-disubstituted isoxazoles 4 of the ethyl-2-benzyl-3-oxo-1-((3-arylisoxazol-5yl)methyl)-2,3-dihydro-1H-isoindole-1-carboxylate type. With aryl azides 2a-d (Ar = Ph, p-MeC 6 H 4 , p-OMeC 6 H 4 , p-ClC 6 H 4 ), a series of 1,4-disubstituted 1,2,3-triazoles 6 (ethyl-2-benzyl-3-oxo-1-((1-aryl-1H-1,2,3-triazol-4-yl)methyl)-2,3-dihydro-1H-isoindole-1-carboxylates) was obtained. The reactions proceed in a regioselective manner affording exclusively racemic adducts 4 and 6. Compared to the uncatalyzed cycloaddition, the yields are significantly improved in the presence of CuI as catalyst, without alteration of the selectivity. The regio-and stereochemistry of the cycloadducts has been corroborated by an X-ray diffraction study of 4a, and in the case of 6a by XH-correlation and HMBC spectra.

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“…While most spermicidal agents from plant extracts act on the sperm surface after inducing disruption of plasma membrane (Lohiya et al, 2000;Souad et al, 2007), there is evidence that nonoxynol-9 completely disrupts the structural integrity of the plasma membrane in human spermatozoa (Gupta et al, 2005;Qiu et al, 2011). …”

Section: Discussionmentioning

confidence: 99%

Effects ofHeliopsis longipesethanolic extract on mouse spermatozoain vitro

Martinez-Loredo

Izquierdo-Vega

Cariño-Cortés

et al. 2015

Pharmaceutical Biology

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Context: Heliopsis longipes (A. Gray) Blake (Asteraceae), a plant native to Mexico, is used in traditional medicine as analgesic and microbicide. The main component in the H. longipes ethanolic extract (HLEE) is affinin, as determined by HPLC/UV-visible and NMR measurement. To date, there is no documented evidence on the spermicidal activity of this extract. Objective: The objective of this study was to assess in vitro the effectiveness of HLEE as spermicide. Materials and methods:The spermicidal activity of HLEE was evaluated by the Sander-Cramer assay. Spermatozoa were incubated for 20 s with HLEE in concentrations ranging from 75 to 2000 mg/mL to determine the minimum effective concentration (MEC) value. The 50% effective concentration (EC 50 ) of HLEE was estimated by assaying serial dilutions from the MEC. Additionally, sperms were incubated with 125, 250, or 500 mg/mL of HLEE to evaluate the viability and the integrity of sperm membrane. Lipid peroxidation was assessed by the thiobarbituric acid reactive substances assay. Results: HLEE caused an inhibition of 100% in spermatozoa motility at a MEC value of 2000 mg/mL; the EC 50 value was 125 mg/mL. Additionally, exposure to HLEE at 125, 250, or 500 mg/mL for 30 min decreased sperm viability to 27%, 8%, and 2% of the control value, respectively, and significantly increased the percentage of sperms with structurally disorganized membrane. HLEE also increased significantly the level of lipid peroxidation in sperms with respect to controls. Discussion and conclusion: The results demonstrate the spermicidal activity of HLEE in vitro and suggest that this action is caused by oxidative damage and alterations in the spermatozoal membrane.

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Discovery of substituted isoxazolecarbaldehydes as potent spermicides, acrosin inhibitors and mild anti-fungal agents

Cited by 30 publications

References 49 publications

Novel Trichomonacidal Spermicides

Novel Trichomonacidal Spermicides

Synthesis of Isoxazole and 1,2,3-Triazole Isoindole Derivatives via Silver- and Copper-Catalyzed 1,3-Dipolar Cycloaddition Reaction

Effects ofHeliopsis longipesethanolic extract on mouse spermatozoain vitro

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