Flavone-Based Novel Antidiabetic and Antidyslipidemic Agents

The hybrid congeners <b>62</b>–<b>90</b> of 6- and 7-hydroxyflavones with aminopropanol have been synthesized and evaluated for their antidiabetic activity in sucrose-challenged low-dosed streptozotocin (STZ)-induced diabetic rats and <i>db/db</i> mice. The optical enantiomers <b>70a</b>, <b>70b</b>, <b>90a</b>, and <b>90b</b> of two congeners <b>70</b> and <b>90</b> exhibiting consistent antidiabetic and antidyslipidemic activities were also prepared, and their antidiabetic activity results indicate its association mainly with S isomers. These compounds also lower cholesterol and TG profiles while improving high-density lipoprotein cholesterol to CHOL ratio in <i>db/db</i> mice. The bioavailability of compound <b>70</b> and its isomer varies between 27 and 29% whereas that of the more polar compound <b>90a</b> is poor as determined in rat by oral and intraperitoneal administrations

Designed Chemical Intervention with Thiols for Prophylactic Contraception

<div><p>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 <i>Trichomonas vaginalis</i>, <i>in vitro</i>. Sperm hexokinase activity was evaluated by coupled enzyme assay. PPC irreversibly immobilized 100% human sperm in ∼30 seconds and totally eliminated <i>Trichomonas vaginalis</i> 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 (<i>in vitro</i>), 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, <i>in vitro</i>. We have thus discovered a common target (reactive thiols) on chiefly-anaerobic, redox-sensitive cells like sperm and <i>Trichomonas</i>, which is susceptible to designed chemical interference for prophylactic contraception. The active thiol in PPC inactivates sperm and <i>Trichomonas</i> 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 <i>Trichomonas</i>, and qualifies as a promising lead for the development of dually protective vaginal-contraceptive.</p></div

The synthesis of pyrrolidinium pyrrolidine-1-carbodithioate (PPC, 3) from pyrrolidine (1) and carbon disulfide (2).

<p>The synthesis of pyrrolidinium pyrrolidine-1-carbodithioate (PPC, 3) from pyrrolidine (1) and carbon disulfide (2).</p

Composition and physical characteristics (Mean±SD) of vaginal film formulations incorporating PPC.

<p>PEG-400 was used as a solubilizer and plasticizer at a final concentration of 2.25 to 5.64%.</p

The <i>in vitro</i> spermicidal and anti-trichomonal activities of pyrrolidinium pyrrolidine-1-carbodithioate (PPC) and its derivatives (BPC, IPC & HPC) with the active thiol blocked by alkylation.

<p>(Mean ± SE of three independent experiments; MEC = minimum effective concentration; MIC = minimum inhibitory concentration).</p

The spermicidal and microbicidal activities of pyrrolidinium pyrrolidine-1-carbodithioate (PPC) in vaginal film formulation and its compatibility with human cervical HeLa cells and <i>Lactobacillus acidophilus</i>, <i>in vitro</i>.

<p>(Mean ± SE of 3 independent experiments; MEC = minimum effective concentration; MIC = minimum inhibitory concentration).</p><p><i>In vitro</i> microbicidal MIC of pure metronidazole = ∼11 & 340 µM against susceptible and resistant strains of <i>T. vaginalis</i>, respectively.</p

Mucoadhesive vaginal contraceptive film incorporating pyrrolidinium pyrrolidinium pyrrolidine-1-carbodithioate (PPC) as active ingredient.

<p>Mucoadhesive vaginal contraceptive film incorporating pyrrolidinium pyrrolidinium pyrrolidine-1-carbodithioate (PPC) as active ingredient.</p

Pyrrolidinium pyrrolidine-1-carbodithioate (PPC) release from mucoadhesive vaginal contraceptive film-formulations F1, F2 and A7, in simulated vaginal fluid (SVF) at 37°C.

<p>Pyrrolidinium pyrrolidine-1-carbodithioate (PPC) release from mucoadhesive vaginal contraceptive film-formulations F1, F2 and A7, in simulated vaginal fluid (SVF) at 37°C.</p

<i>In vivo</i> contraceptive efficacy of PPC vaginal films in rabbits.

<p><i>In vivo</i> contraceptive efficacy of PPC vaginal films in rabbits.</p