Effect of abouthiouline, a novel drug with therapeutic potential as antithyroid, on some biochemical and hematologic parameters in mice and rats

Abouthiouline [1-Cyclohexyl-3[3-quinolyl]-2-thiourea] is a novel compound with antithyroid activity. Abouthiouline [ABL] was designed based on structure-activity relationships [E-state indexes] aimed at reducing the antioxidant properties of the compound by modification of acyclic thiourylene moiety. Antioxidant effects of currently available treatments such as propylthiouracil [PTU], methimazole [MTM] are associated with an incidence of agranulocytosis and aplastic anemia. In the present study, the preclinical toxicology of ABL was determined in mice and rats and compared with two reference compounds, namely, propylthiouracil, methimazole. Following short-term administration [7 days] to mice, ABL had minimal effects on biochemical parameters, although significant reductions in both total protein and albumin were noted. Long-term studies [30 days] in rats revealed significant effects of Abouthiouline, propylthiouracil and methimazole on serum electrolyte and glucose levels. Abouthiouline had no detrimental effects on hematologic parameters. However, total WBC count [propylthiouracil] and neutrophil levels [propylthiouracil and methimazole] were significantly decreased among other treatment groups. The results of this investigation suggest that Abouthiouline is a promising new antithyroid therapy with a reduced risk of hematologic toxicity that is associated with PTU and MTM. Further studies are warranted to assess the safety and efficacy of Abouthiouline

Atom level electrotopological stste indexes of thiourylene-type compounds and their antioxidant/oxidant properties: a novel immunoregulatory-guideline

In this study, we tried to establish a relationship between the antioxidant/oxidant property of thiourylene-type compounds and their electrotopological-state [E-state] indexes of thiourylene moiety [SN and S] for different concentrations. Such relationship could be used as a guideline in modulating the immunoregulatory effect prior to the synthesis of new thiourylene-type compounds. The chemiluminescence studies on activated polymorphonuclear leukocytes [PMNLs] were utilized to reveal the antioxidant/oxidant status of a series of thiourylene-type compounds. Results indicate that [1] Not all the thiourylene-type compounds are antioxidants and their antioxidant/oxidant properties varies with the electronic accessibility on the thiourylene moiety as influenced by molecular topology, resonance and steric hindrance by the N-substituents. [2] In case of the compounds containing pure thiourylene moiety, [SN and S] increases with the increase of the oxidant property of the compounds in a linear relationship. [3] In case of compounds such as thiosemicarbazone, electronic accessibility on the S[N and S]and the adjacent nitrogen S[N] was found to be additive and the E-state of S[N and S] + S[N] was related to the oxidant property of the compounds. Thus, emphasizing the importance of thiosemicarbazone moiety in the antithyroid therapy. [4] The antioxidant property of thiourylene-type compounds was reversed at higher concentration with variable magnitude due to the relative accumulation of the stable thiyl pro-oxidant ion. In conclusion, the E-state approach is suitable for establishing guidelines that economize efforts and cost of developing therapeutic agents with the desired immunoregulatory effect

Oxidative stress, HIV and aids: the basis for antioxidant-oriented antiretroviral nucleoside analogues

The HIV seropositive patients are under systemic and intracellular oxidative stress as a result of an excessive production of reactive oxygen species [ROS] combined with the deficiencies of endogenous antioxidants such as glutathione [GSH], cysteine, vitamin E, carotenoids, zinc manganese containing superoxide dismutase [Mn-SOD], selenium containing GSH peroxidase and catalase in the T-cell subsets. The different sources of ROS in AIDS patients are the activated leucocytes, cytokines and drugs required to control HIV progression, associated infections and cancers. Several reports suggest the involvement of ROS activated cytoplasmic factors such as nuclear factor kB [NF-KB] and tumor necrosis factor Alpha [TNF-Alpha] in the regulation of HIV replication. Since the discovery of retroviral cause for AIDS, a wide variety of agents capable of inhibiting different sites of viral life cycle were discovered. These agents were found to possess diverse chemical structures and works on different viral or host targets. The viral targets are either specific enzymes [reverse transcriptase, protease or glucosidase] or viral processes [gene expression viral binding or viral budding] which interfere with the viral multiplication. The retroviral reverse transcriptase has been a popular target for the design and synthesis of anti HIV drugs. Recent studies have focused on an intracellular target, the NF kB, whose stimulation is related to the lowering of the endogenous antioxidant defense system and stimulation of the HIV expression. Inspite of the myriad of the myriad of known synthetic and/or natural inhibitors of HIV over the last decade, the AIDS virus still successfully elude all forms of curative therapy. Replenishing antioxidants will have a preventive role in different stages of AIDS disease, associated infections and cancers. The beneficial effect of free radical scavengers depend on biological compatibility, the dosage used and the appropriate delivery systems that will allow the scavenger to act at the cellular and tissue sites where the free radicals are interfering with the normal function and causing injury. In this report, the author wishes to review the justification for a novel anti-AIDS class antioxidant oriented antiretroviral nucleoside analogues that might provide curative therapy. These drugs will act by inhibiting both the reverse transcriptase viral target and host mediated stimulation of viral replication. Accordingly the prospective compounds will block the formation of provirus, extend the latency after HIV integration into host genome, and inhibit viral expression. The required structural specification will be discussed. In addition the positive effect of the prospective drugs that might lead to the curative therapy are also outlined

Development of new antithyroid compounds with reduced antioxidant property

Based on literature evaluation, we hypothesize that in order to control graves disease and the onset of drug induced agranulocytosis the trends in antithyroid therapy should be modified to include acyclic thiourea with reduced anioxidant property. A linear relationship was developed between percentage of inhibition of luminol enhanced chemiluminescence [%CL] of stimulated polymorphonuclear leucocytes [PMNLs] obtained from Imamura et al. [Acta Endocrinological, 1986; 112:210-216.] data of currently used antithyroids and related compounds and their atom level electrotopological state [E-state] indexes of their thiourylene moiety [S[N AND S]]. The resulted relationship [% CL inhibition = 349.254 [ +/- 8.52] -37.692 [ +/- 1.13] [S[N AND S]; = 0.999; SEM = 0.47; F= 1108.1; P = 0.019] was utilized as a guideline for the rational selection of thiourylene type compounds [with S[N and S] >8] with reduced antioxidant property. The compounds selected were evaluated for their antioixdant property utilizing their influence on luminol-enhanced chemiluminescence [CL] of phorbol myristate acetate [PMA] induced human PMNLs and was found to agree with the guideline extracted from Imamura et al data. The formation of the selected compounds of their charge transfer complex with iodine was determined spectroscopically and utilized as a primary criteria for their potential antithyroid activity. In addition, these agents were screened for antithyroid activity in rats using [125] I-thiocyanate discharge technique. The relative efficacy [in relation to equimolar dose of propylthiouracil] of the tested agents with respect to both [125] I-uptake and the rate of [125] I-discharge were determined and proved that at least one of the three investigated compounds [abouthiouline] has higher antithyroidal activity than propylthiouracil with respect to the rate of [125] I-discharge. The relative efficacy of abouthiouline [1-cyclohexy1-3[3-quinoly1]-2-thiourea], after equimolar dose was 131.13% and 51.72% of that of propylthiouracil with respect to the rate of [125] I-discharge and [125] I-uptake respectively. The importance of the thyroid [125] I-discharge in antithyroid therapy in reducing the dose and the duration of treatment is discussed. Since the ratio of the percent efficacy with respect to the rate of [125] I-discharge to [125] I-uptake of abouthiouline is 2.54, it is perceived that abouthiouline is of potential value as antithyroid agent after adjusting the dose with respect to the therapeutic dose of propylthiouracil. In conclusion, abouthiouline has lower toxicity [LD[50] >800 mg/kg] reduced antioxidant property as well as higher antithyroidal efficacy than propylthiouracil with respect to the rate of 125I discharge. In view of the toxic omplications of the antioxidant property of the currently used antithyroid agents it is suggested that abouthiouline will be beneficial in reducing the severity of the immune reaction of both the Graves disease and the drug induced agranulocytosis. Further supportive investigations are in progress