RESUMO
BACKGROUND: In our previous work, several piperazine derived bis(dialkylaminethiocarbonyl) disulfides and disulfide esters of dithiocarbamic acid have been synthesized and evaluated for their spermicidal and microbicidal efficacy. These studies have provided some promising compounds for developing a dually active vaginal microbicidal contraceptive which is under pre-clinical stage. OBJECTIVE: The main objective of this study was the design synthesis and biological evaluation of bis(dialkylaminethiocarbonyl) disulfides (4-15) and 2,2'-disulfanediylbis (3-(substituted-1-yl) propane-2,1-diyl) disubstituted-1-carbodithioates (19-28) as non-surfactant molecules capable of eliminating Trichomonas vaginalis as well as irreversibly immobilizing 100% human sperm promptly. METHOD: Spermicidal, anti-trichomonas, cytotoxicity and biocompatibility study of the synthesized compounds was done as per the reported methodologies. RESULT: Among bis(dialkylaminethiocarbonyl) disulfides (4-15, Table 1), compound 4 (MEC 0.02 mM) was found to be the most desirable for spermicidal activity as it was 40 times more active than Nonoxynol-9 (N-9), and also active against Trichomonas vaginalis (MIC 0.02 &1.10 mM). 2, 2'-disulfanediylbis (3-(substituted- 1-yl) propane-2, 1-diyl) disubstituted-1-carbodithioates (19-28, Table 2), and compounds (19, 22, 23, and 24 MEC 0.05 mM) were sixteen times more active than N-9 with promising Trichomonacidal activity. CONCLUSION: This study suggested that the disulfide linkage alone and dithiocarbamate along with disulfide group within the same chemical entity impart the desired multiple activities of compounds.
Assuntos
Antitricômonas/farmacologia , Dissulfetos/farmacologia , Compostos Heterocíclicos com 1 Anel/farmacologia , Espermicidas/farmacologia , Tiocarbamatos/farmacologia , Antitricômonas/síntese química , Dissulfetos/síntese química , Desenho de Fármacos , Células HeLa , Compostos Heterocíclicos com 1 Anel/síntese química , Humanos , Lactobacillus acidophilus/efeitos dos fármacos , Masculino , Testes de Sensibilidade Microbiana , Nonoxinol/farmacologia , Espermicidas/síntese química , Espermatozoides/efeitos dos fármacos , Relação Estrutura-Atividade , Tiocarbamatos/síntese química , Trichomonas vaginalis/efeitos dos fármacosRESUMO
The growing population and health-care burden (due to STIs and HIV) imposes a particular economic crisis over resource-poor countries. Thus a novel approach as vaginal microbicides emerges as integrated tool to control both population and anti-STIs/HIV. Our continued efforts in this field led to the synthesis of fifteen N-alkyl/aryl-4-(3-substituted-3-phenylpropyl) piperazine-1-carbothioamide (12-26) derivatives as topical vaginal microbicides which were evaluated for anti-Trichomonas, spermicidal, antifungal and reverse transcriptase (RT) inhibitory activities. All compounds were also tested for preliminary safety through cytotoxicity assays against human cervical cell line (HeLa) and the vaginal flora, Lactobacillus. Docking studies were performed to gain an insight into the binding mode and interactions of the most promising compound 12 [oxo derivative], comprising of reverse transcriptase (RT) inhibitory (72.30%), spermicidal (MEC 0.01%), anti-Trichomonas (MIC 46.72 µM) and antifungal (MIC 9.34-74.8 µM) activities, along with its hydroxyl (17) and O-alkylated 4-trifluoromethylphenoxy (22) derivative, with similar activities. The stability of compound 12 in simulated vaginal fluid (SVF) and its preliminary in vivo pharmacokinetics performed in female NZ-rabbits signifies its clinical safety in comparison to marketed spermicide Nonoxynol-9.
Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Piperazinas/farmacologia , DNA Polimerase Dirigida por RNA/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Espermicidas/farmacologia , Tioamidas/farmacologia , Vagina/efeitos dos fármacos , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Relação Dose-Resposta a Droga , Feminino , Células HeLa , Humanos , Lactobacillus acidophilus/efeitos dos fármacos , Masculino , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Testes de Sensibilidade Parasitária , Piperazinas/síntese química , Piperazinas/química , Coelhos , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Espermicidas/síntese química , Espermicidas/química , Espermatozoides/efeitos dos fármacos , Relação Estrutura-Atividade , Tioamidas/síntese química , Tioamidas/química , Trichomonas vaginalis/efeitos dos fármacosRESUMO
A series of seventeen morpholin/piperidin-1-yl-carbamodithioate (3-19) were synthesized as topical vaginal microbicidal spermicides. The synthesized compounds were evaluated for their anti-Trichomonas activity against MTZ susceptible and resistant strains along with their spermicidal and antifungal potential. All the synthesized compounds were assessed for their safety through cytotoxic assay against human cervical cell line (HeLa) and compatibility with vaginal flora, Lactobacillus. The study identified eleven dually active compounds with apparent safety. The plausible mode of action of these compounds was through sulfhydryl binding, confirmed via reduction in available free thiols on human sperm. The most promising compound 9 significantly inhibited (P<0.001) thiol-sensitive sperm hexokinase. The stability of compound 9 in simulated vaginal fluid (SVF) was performed via HPLC-PDA method, which supported its utility for vaginal administration.
Assuntos
Antifúngicos/síntese química , Desenho de Fármacos , Piperidinas/síntese química , Espermicidas/síntese química , Compostos de Sulfidrila/química , Tiocarbamatos/síntese química , Antifúngicos/farmacologia , Antifúngicos/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Feminino , Células HeLa , Hexoquinase/antagonistas & inibidores , Hexoquinase/metabolismo , Humanos , Lactobacillus/efeitos dos fármacos , Masculino , Testes de Sensibilidade Microbiana , Morfolinas/química , Piperidinas/química , Piperidinas/farmacologia , Piperidinas/toxicidade , Espermicidas/farmacologia , Espermicidas/toxicidade , Espermatozoides/efeitos dos fármacos , Espermatozoides/enzimologia , Relação Estrutura-Atividade , Compostos de Sulfidrila/farmacologia , Compostos de Sulfidrila/toxicidade , Tiocarbamatos/farmacologia , Tiocarbamatos/toxicidade , Trichomonas vaginalis/efeitos dos fármacosRESUMO
Dithiocarbamates are considered as the simplest occurring organosulfur compounds exhibiting diverse chemical and medicinal versatility. Dithiocarbamates have been used as pesticide in the 20(th) century but thereafter they have attracted the interest of medicinal chemists due to their metal binding capacity. Recently a variety of chemical and medicinal properties of dithiocarbamates have been explored other than metal binding capacity. This review collectively describes the most significant chemical and medicinal properties of dithiocarbamate derivatives reported over the last decade.
Assuntos
Descoberta de Drogas , Tiocarbamatos/química , Tiocarbamatos/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , HIV/efeitos dos fármacos , Humanos , Micoses/tratamento farmacológico , Neoplasias/tratamento farmacológico , Espermicidas/síntese química , Espermicidas/química , Espermicidas/farmacologia , Tiocarbamatos/síntese químicaRESUMO
A series of γ-butyrolactone derivatives has been designed and synthesized from commercially available 2-acetyl butyrolactone (3-acetyldihydrofuran-2(3H)-one, 1) by aminoalkylating its active methylene followed by condensation with different aldehydes. Compounds having amino group were further converted to their respective tartrate salts and were evaluated for spermicidal activity against human sperm in vitro. Compounds showing appreciable spermicidal activity at ⩽0.5% [3c, 4d (0.5%); 2c, 3d (0.1%); 2d, 4c (0.05%)] were tested for safety studies against human cervical (HeLa) cell line. These compounds were found safer than, Nonoxynol-9. One of the two most active compounds was also found to be the safest (IC50=961 µg/ml; 4c), while the second compound exhibited lower safety against HeLa (IC50=269 µg/ml; 2d). The compound 4c significantly reduced the number of free thiols on human sperm. All the compounds were inactive against Trichomonas vaginalis.
Assuntos
4-Butirolactona/farmacologia , Desenho de Fármacos , Espermicidas/farmacologia , Espermatozoides/efeitos dos fármacos , 4-Butirolactona/síntese química , 4-Butirolactona/química , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Masculino , Estrutura Molecular , Espermicidas/síntese química , Espermicidas/química , Espermatozoides/química , Relação Estrutura-Atividade , Compostos de Sulfidrila/antagonistas & inibidores , Trichomonas vaginalis/efeitos dos fármacosRESUMO
We designed a series of 25 3-(azol-1-yl)phenylpropanes which yielded 10 compounds (3, 4, 7, 8, 13, 14, 19, 21, 23, 26) that irreversibly immobilized 100% human sperm at 1% (w/v) concentration in 60s; 12 compounds (8, 9, 15, 16, 19-21, 23-25, 27, 28) that showed potent microbicidal activity at 12.5-50 µg/mL against Trichomonas vaginalis; and 17 compounds (3-11, 13, 15, 19, 21, 23, 26, 28, 30) that exhibited potent anticandida activity with minimum inhibitory concentration (MIC) of 12.5-50 µg/mL. Almost all the compounds exhibited high level of safety towards normal vaginal flora (Lactobacillus) and human cervical (HeLa) cells in comparison to the marketed spermicide nonoxynol-9 (N-9). All the biological activities were evaluated in vitro. Two compounds (4, 8) with good safety profile exhibited multiple (spermicidal, antitrichomonas and anticandida) activities, warranting further lead optimization for furnishing a prophylactic vaginal contraceptive.
Assuntos
Anti-Infecciosos/síntese química , Antifúngicos/síntese química , Anticoncepcionais Femininos/síntese química , Propano/química , Espermicidas/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/toxicidade , Antifúngicos/química , Antifúngicos/toxicidade , Anticoncepcionais Femininos/química , Anticoncepcionais Femininos/toxicidade , Desenho de Fármacos , Feminino , Células HeLa , Humanos , Lactobacillus/efeitos dos fármacos , Propano/síntese química , Propano/toxicidade , Espermicidas/química , Espermicidas/toxicidade , Relação Estrutura-Atividade , Trichomonas vaginalis/efeitos dos fármacosRESUMO
Syntheses of 3,3-diheteroaromatic oxindole derivatives has been achieved by coupling indole-2,3-dione (isatin) with differently substituted indoles and pyrrole in presence of I(2) in i-PrOH. The in vitro spermicidal potentials and the mode of spermicidal action of the synthesized analogues were evaluated and the derivative, 3,3-bis (5-methoxy-1H-indol-3-yl) indolin-2-one (3d) exhibited most significant activity.
Assuntos
Indóis/química , Indóis/síntese química , Espermicidas/síntese química , Animais , Indóis/farmacologia , Microscopia Eletrônica de Transmissão , Oxindóis , Ratos , Espermicidas/química , Espermicidas/farmacologiaRESUMO
S,S'-[disulfanediylbis(dialkylaminopropane-2,1-diyl)]bis- (dialkylaminothiocarbamate) (14-31) were prepared and evaluated for the spermicidal activity and antifungal activity. Dialkyldithiocarbamates (1-5) were reacted with epichlorohydrin to give 1-dialkylaminocarbothioic acid S-[(2,3-epithio)propyl]ester (7-11), these on further reaction with a secondary amine gave S,S'-[disulfanediylbis(dialkylaminopropane-2,1-diyl)]bis- (dialkylaminothiocarbamate) (14-31). Some of these compounds (16, 19-21, 23, 30, 31) were found to be very potent spermicidal agents with marginal antifungal activity. Two compounds (20, 21) were 25 times more active than nonoxynol-9 (N-9), the spermicide currently in the market.
Assuntos
Antifúngicos/química , Antifúngicos/farmacologia , Dissulfetos/química , Dissulfetos/farmacologia , Etilaminas/química , Sêmen/efeitos dos fármacos , Espermicidas/química , Espermicidas/farmacologia , Compostos de Sulfidrila/química , Antifúngicos/síntese química , Dissulfetos/síntese química , Humanos , Masculino , Contagem de Espermatozoides , Motilidade dos Espermatozoides/efeitos dos fármacos , Espermicidas/síntese químicaRESUMO
Fifteen analogues of benzenepropanamine were synthesized and evaluated for their spermicidal as well as microbicidal activities against Trichomonas vaginalis and Candida spp. Several compounds showed appreciable dual activities. Compound 12 exhibited good spermicidal (MEC=0.1%) along with substantial anticandidal (MIC=0.05%) activities, while compounds 3 and 6 showed significant microbicidal activities with moderate spermicidal effect. The SAR of these structures is being discussed here in this communication. It is concluded that suitable structural modifications in this class of compounds at 3-amino position may lead to a potent spermicide with associated microbicidal activity.
Assuntos
Aminas/farmacologia , Antifúngicos/síntese química , Antifúngicos/farmacologia , Antitricômonas/síntese química , Antitricômonas/farmacologia , Derivados de Benzeno/farmacologia , Espermicidas/síntese química , Espermicidas/farmacologia , Adulto , Aminas/química , Animais , Antifúngicos/química , Antitricômonas/química , Derivados de Benzeno/química , Candida albicans/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fenômenos Químicos , Físico-Química , Humanos , Técnicas In Vitro , Masculino , Testes de Sensibilidade Microbiana , Espectroscopia de Infravermelho com Transformada de Fourier , Espermicidas/química , Espermatozoides/efeitos dos fármacos , Relação Estrutura-Atividade , Trichomonas vaginalis/efeitos dos fármacosRESUMO
Most heterosexual women want to reduce the risk of acquiring a sexually transmitted infection; many also want to control their fertility. Several chemical agents have been proposed to dramatically slow the spread of HIV infections. Ideally, vaginal microbicides, with or without contraceptive properties, should be safe, effective, and affordable for women everywhere. Amphiphiles, which are surfactants that can act as detergents, have a long history as microbicides against many pathogens. Amphiphiles have several desirable traits; e.g., they are inexpensive, fast-acting, and capable of a broad spectrum of activity. An "ideal" amphiphilic microbicide will rapidly and selectively inactivate pathogens and sperm without irritating tissue. In this review, we discuss a homologous series of amphiphilic acylcarnitine analogues as microbicides. Two homologues, Z-14 and Z-15, possess excellent spermicidal, anti-HIV, anti-chlamydial, anti-gonorrhea, and anti-Haemophilus activities; both have outstanding anti-Candida activity. A 4% Z-15 gel that is comprised of 3% carboxymethylcellulose in water gives a dramatically low score in a rabbit-vaginal-irritation study. The mechanisms of action of these compounds are not fully understood as yet, but we present several possibilities. Moreover, the results of our limited structure-activity study with a homologous series have stimulated additional questions and ideas for designing the next generation of microbicidal amphiphiles. The above studies support the idea that Z-14 and Z-15 can potentially serve as safe (non-irritating), effective topical microbicides.
Assuntos
Anti-Infecciosos Locais/síntese química , Anti-Infecciosos Locais/farmacologia , Carnitina/análogos & derivados , Carnitina/síntese química , Animais , Carnitina/farmacologia , Fenômenos Químicos , Físico-Química , Desenho de Fármacos , Humanos , Espermicidas/síntese química , Espermicidas/farmacologiaRESUMO
Several appropriately substituted 4-(dialkylamino-alkyl)-substituted-styryl-alkyl ketones or acetophenones were prepared and subjected to the Mannich reaction to yield compounds that would incorporate both alpha,beta-unsaturated keto groups and a substituted aminomethyl function with or without another olefinic moiety at position 4. The spermicidal activity of the prepared compounds was evaluated. Several compounds 2d, 4a and 4e were found to possess spermicidal activity at 0.005% concentration, while compounds 2a, 2c, 2f, 3a and 4b were active at 0.01% concentration. Compounds 2a, 2c, 3a, 4a and 4e also inhibited the interaction between recombinant HIV Env and CD4. Out of these, compound 2c was found to be most active.
Assuntos
Fármacos Anti-HIV/síntese química , Proteína gp160 do Envelope de HIV/efeitos dos fármacos , Espermicidas/síntese química , Fármacos Anti-HIV/farmacologia , Derivados de Benzeno/síntese química , Derivados de Benzeno/farmacologia , Antígenos CD4/metabolismo , Linhagem Celular Transformada , Proteína gp160 do Envelope de HIV/metabolismo , Humanos , Cetonas/síntese química , Cetonas/farmacologia , Masculino , Bases de Mannich/síntese química , Bases de Mannich/farmacologia , Ligação Proteica/efeitos dos fármacos , Espermicidas/farmacologia , Espermatozoides/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
In a systematic effort to develop a microbicide contraceptive capable of preventing transmission of human immunodeficiency virus (HIV), as well as providing fertility control, we have previously identified novel phenyl phosphate derivatives of zidovudine (ZDV) with 5-halo 6-alkoxy substitutions in the thymine ring and halo substitution in the phenyl moiety respectively. Here, we describe the synthesis, characterization, and successful preclinical formulation of our lead compound, 5-bromo-6-methoxy-3'-azidothymidine-5'-(p-bromophenyl) methoxyalaninyl phosphate (WHI-07), which exhibits potent anti-HIV and sperm immobilizing activities. The anti-HIV activity of WHI-07 was tested by measuring viral p24 antigen production and reverse transcriptase activity as markers of viral replication in HIV-1 infected human peripheral blood mononuclear cells (PBMC). WHI-07 inhibited replication of HIV in a concentration-dependent fashion with nanomolar IC50 values. The effects of WHI-07 on human sperm motion kinematics were analysed by computer-assisted sperm analysis (CASA), and its effects on sperm membrane integrity were examined by confocal laser scanning microscopy (CLSM), and high-resolution low-voltage scanning electron microscopy (HR-LVSEM). WHI-07 caused cessation of sperm motility in a concentration- and time-dependent fashion. The in-vitro cytotoxicities of WHI-07 and nonoxynol-9 (N-9) were compared using normal human ectocervical and endocervical epithelial cells by the MTT cell viability assay. Unlike N-9, WHI-07 had no effect upon sperm plasma and acrosomal membrane integrity. N-9 was cytotoxic to normal human ectocervical and endocervical cells at spermicidal doses, whereas WHI-07 was selectively spermicidal. The in-vivo vaginal absorption and vaginal toxicity of 2% gel-microemulsion of WHI-07 was studied in the rabbit model. The sperm immobilizing activity of WHI-07 was 18-fold more potent than that of N-9. Over a 10 day period, there was no irritation or local toxicity to the vaginal epithelia or systemic absorption of WHI-07. Therefore, as a potent anti-HIV agent with spermicidal activity, and lack of mucosal toxicity, WHI-07 may have the clinical potential to become the active ingredient of a vaginal contraceptive for women who are at high risk for acquiring HIV by heterosexual vaginal transmission.
Assuntos
Fármacos Anti-HIV/farmacologia , Espermicidas/farmacologia , Timidina Monofosfato/análogos & derivados , Zidovudina/análogos & derivados , Reação Acrossômica/efeitos dos fármacos , Animais , Fármacos Anti-HIV/síntese química , Membrana Celular/efeitos dos fármacos , Colo do Útero/citologia , Colo do Útero/efeitos dos fármacos , Didesoxinucleotídeos , Avaliação Pré-Clínica de Medicamentos , Emulsões/química , Emulsões/farmacologia , Células Epiteliais/efeitos dos fármacos , Feminino , HIV-1/efeitos dos fármacos , Humanos , Masculino , Coelhos , Motilidade dos Espermatozoides/efeitos dos fármacos , Espermicidas/síntese química , Espermatozoides/efeitos dos fármacos , Timidina Monofosfato/síntese química , Timidina Monofosfato/farmacologia , Vagina/efeitos dos fármacos , Vagina/patologia , Replicação Viral/efeitos dos fármacos , Zidovudina/síntese química , Zidovudina/química , Zidovudina/farmacologiaRESUMO
We synthesized a novel compound, 5-bromo-6-methoxy-5,6-dihydro-AZT-5'- (p-bromophenyl methoxyalaninyl phosphate), which had an EC50 value of 5 microM in sperm motility assays. This is > 1 log10 better than that of the detergent spermicide nonoxynol-9 (EC50 81 microM). The compound also displayed a potent anti-human immunodeficiency virus (HIV) activity with an IC50 value of 0.005 microM in HIV replication assays, which was virtually identical to that of AZT (IC50 0.006 microM) and > 2 log10 more potent than that of nonoxynol-9 (IC50 2.2 microM). The promising results reported herein recommend the further development of the dual function 5-halo-6-alkoxyl-5,6-dihydro-AZT derivatives as a new class of vaginal contraceptives capable of preventing the sexual transmission of HIV while providing fertility control for women who are at high risk of acquiring HIV by heterosexual transmission. These dual function 5-halo-6-alkoxyl-5,6-dihydro-AZT derivatives may also have utility in curbing domestic and wildlife animal retroviral transmissions.
Assuntos
Compostos Organofosforados/síntese química , Zidovudina/análogos & derivados , Zidovudina/síntese química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Dispositivos Anticoncepcionais Femininos , Didesoxinucleotídeos , Feminino , HIV/efeitos dos fármacos , Infecções por HIV/prevenção & controle , Humanos , Masculino , Nonoxinol/farmacologia , Compostos Organofosforados/farmacologia , Espermicidas/síntese química , Espermicidas/farmacologia , Espermatozoides/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Zidovudina/farmacologiaRESUMO
Several compounds belonging to 2-isoxazolines (4,5a-c), isoxazoles (3,6a-c) and 1-amino-1-cycloalkyl-2-substituted phenyl ethanes (16-18,a-e) have been synthesised and found to possess spermicidal activity. Out of these a couple of compounds (5a and 6a) exhibit anti-HIV activity.