Design and synthesis of 3-(azol-1-yl)phenylpropanes as microbicidal spermicides for prophylactic contraception

Kumar, Lalit; Sarswat, Amit; Lal, Nand; Jain, Ashish; Kumar, Sumit; Kumar, S.T.V.S. Kiran; Maikhuri, Jagdamba P.; Pandey, A. K.; Shukla, Praveen Kumar; Gupta, Gopal; Sharma, Vishnu L.

doi:10.1016/j.bmcl.2010.11.042

Cited by 18 publications

(12 citation statements)

References 23 publications

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“…Notably, it caused 100% immobilization of human sperm at 1% concentration comparable to nonoxynol‐9 (100%) and also exhibited anti‐ Candida activities. Further research disclosed that the relative position of the carbonyl group and nitroimidazole ring was optimal for dual activity and safety . Compound 169 provides the possibility to be developed as a potent dually active microbicidal spermicide.…”

Section: Imidazoles As Antiparasitic Agentsmentioning

confidence: 99%

Comprehensive Review in Current Developments of Imidazole-Based Medicinal Chemistry

et al. 2013

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Imidazole ring is an important five-membered aromatic heterocycle widely present in natural products and synthetic molecules. The unique structural feature of imidazole ring with desirable electron-rich characteristic is beneficial for imidazole derivatives to readily bind with a variety of enzymes and receptors in biological systems through diverse weak interactions, thereby exhibiting broad bioactivities. The related research and developments of imidazole-based medicinal chemistry have become a rapidly developing and increasingly active topic. Particularly, numerous imidazole-based compounds as clinical drugs have been extensively used in the clinic to treat various types of diseases with high therapeutic potency, which have shown the enormous development value. This work systematically gives a comprehensive review in current developments of imidazole-based compounds in the whole range of medicinal chemistry as anticancer, antifungal, antibacterial, antitubercular, anti-inflammatory, antineuropathic, antihypertensive, antihistaminic, antiparasitic, antiobesity, antiviral, and other medicinal agents, together with their potential applications in diagnostics and pathology. It is hoped that this review will be helpful for new thoughts in the quest for rational designs of more active and less toxic imidazole-based medicinal drugs, as well as more effective diagnostic agents and pathologic probes.

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Section: Imidazoles As Antiparasitic Agentsmentioning

confidence: 99%

Comprehensive Review in Current Developments of Imidazole-Based Medicinal Chemistry

et al. 2013

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“…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).…”

mentioning

confidence: 99%

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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“…This study was approved by the Institutional Ethics Committee for Human Research and prior informed written consent was obtained from the donors for this study. The spermicidal assay of pure compound has been reported earlier [17]. The minimum effective (spermicidal) concentration (MEC) of the active ingredient (PPC) in vaginal film was determined by the modified Sander-Cramer assay [14], [20].…”

Section: Methodsmentioning

confidence: 99%

“…Equally important, T. vaginalis lacks glutathione (the intracellular redox buffer), glutathione dependent peroxidase, and catalase, and therefore it relies heavily on cysteine (which constitutes >70% of cell’s total thiol pool) for protection against redox-stress, making it extremely susceptible to sulfhydryl-manipulating agents [11]. Thus, exploiting thiols as a common target on both sperm and Trichomonas we designed several dually active, non-surfactant molecular prototypes for prophylactic contraception [12]–[17]. However, a perfect balance of the two activities could not be achieved optimally.…”

Section: Introductionmentioning

confidence: 99%

Designed Chemical Intervention with Thiols for Prophylactic Contraception

et al. 2013

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Unlike somatic cells, sperm have several-fold more available-thiols that are susceptible to redox-active agents. The present study explains the mechanism behind the instant sperm-immobilizing and trichomonacidal activities of pyrrolidinium pyrrolidine-1-carbodithioate (PPC), a novel thiol agent rationally created for prophylactic contraception by minor chemical modifications of some known thiol drugs. PPC, and its three derivatives (with potential active-site blocked by alkylation), were synthesized and evaluated against live human sperm and metronidazole-susceptible and resistant Trichomonas vaginalis, in vitro. Sperm hexokinase activity was evaluated by coupled enzyme assay. PPC irreversibly immobilized 100% human sperm in ∼30 seconds and totally eliminated Trichomonas vaginalis more efficiently than nonoxynol-9 and metronidazole. It significantly inhibited (P<0.001) thiol-sensitive sperm hexokinase. However, the molecule completely lost all its biological activities once its thiol group was blocked by alkylation. PPC was subsequently formulated into a mucoadhesive vaginal film using GRaS excipients and evaluated for spermicidal and microbicidal activities (in vitro), and contraceptive efficacy in rabbits. PPC remained fully active in quick-dissolving, mucoadhesive vaginal-film formulation, and these PPC-films significantly reduced pregnancy and fertility rates in rabbits. The films released ∼90% of PPC in simulated vaginal fluid (pH 4.2) at 37°C in 5 minutes, in vitro. We have thus discovered a common target (reactive thiols) on chiefly-anaerobic, redox-sensitive cells like sperm and Trichomonas, which is susceptible to designed chemical interference for prophylactic contraception. The active thiol in PPC inactivates sperm and Trichomonas via interference with crucial sulfhydryl-disulfide based reactions, e.g. hexokinase activation in human sperm. In comparison to non-specific surfactant action of OTC spermicide nonoxynol-9, the action of thiol-active PPC is apparently much more specific, potent and safe. PPC presents a proof-of-concept for prophylactic contraception via manipulation of thiols in vagina for selective targeting of sperm and Trichomonas, and qualifies as a promising lead for the development of dually protective vaginal-contraceptive.

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Design and synthesis of 3-(azol-1-yl)phenylpropanes as microbicidal spermicides for prophylactic contraception

Cited by 18 publications

References 23 publications

Comprehensive Review in Current Developments of Imidazole-Based Medicinal Chemistry

Comprehensive Review in Current Developments of Imidazole-Based Medicinal Chemistry

Novel Trichomonacidal Spermicides

Designed Chemical Intervention with Thiols for Prophylactic Contraception

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