Anti-Infective Agents - Volume 14, Issue 1, 2016

Background: Molecular structure is the basis for establishing of quantitative structure –activity relationships (QSARs). The molecular graph as well as the simplified molecular input line entry systems (SMILES) are possible ways to represent the molecular structure for QSAR analysis by means of the CORAL software. Methods: In spite of apparent influence of distribution of available data on the training set and validation set, the majority of works dedicated to quantitative structure - property/activity relationships (QSPRs/QSARs) are based solely on one split into visible set (i.e. the training set) and invisible set (i.e. the validation set). We deem that each QSAR approach should be estimated for a group of splits into the training set and validation set. The use of this principle for the case of antituberculosis agents is the essence of this work. Results: Ten splits of the data on anti-tuberculosis agents into the training and test sets have been examined. The statistical approach to define the domain of applicability has been suggested and estimated. A collection of molecular structures which should be very effective anti-tuberculosis agents according to the established model is suggested. Conclusion: The CORAL software available on the Internet can be used for the QSAR analysis of other molecular structures which are capable anti-infective agents.

Background: Malaria is a leading cause of death and disease in many developing countries, where young children and pregnant women are the most affected groups. In 2012, there were an estimated 207 million cases of malaria, which caused approximately 627 000 malaria deaths. Around 80% of malaria cases occur in Africa, where the lack of access to malaria diagnosis is largely due to a shortage of expertise, being the shortage of equipment the secondary factor. This lack of expertise for malaria diagnosis frequently results on the increase of false positives, since prescription of medication is based only on symptoms. Thus, there is an urgent need of new tools that can facilitate the rapid and easy diagnosis of malaria, especially in areas with limited access to quality healthcare services. Methods: Various image processing and analysis approaches already proposed on the literature for the detection and segmentation of malaria parasites in blood smear microscopic images were collected and reviewed. This timely review aims to support the increasing interest in the development of low cost tools that can facilitate the rapid and easy diagnosis of malaria, especially in areas with limited access to quality healthcare services. Results: Malaria parasites detection and segmentation techniques in microscopic images are, in general, still in need of improvement and further testing. Most of the methodologies reviewed in this work were tested with a limited number of images, and more studies with significantly larger datasets for the evaluation of the proposed approaches are needed. Despite promising results reported during the past years, the great majority of the computer-aided methods found on the literature for malaria diagnosis are based on images acquired under well controlled conditions and with proper microscopic equipment. However, one should take into account that 80% of malaria cases occur in Africa, where this type of equipment is scarce or even nonexistent in common healthcare facilities. Conclusion: This work collects and reviews various image processing and analysis approaches already proposed on the literature for the detection and segmentation of malaria parasites in blood smear microscopic images. This timely review aims to support the increasing interest in the development of image processing-based systems to be used in rural areas of developing countries, which might be the next future trend in malaria computer-aided diagnosis.

Background: The mucosal formulations are required to be evaluated for their safety and irritability. In present study the safety and irritability potential of antimicrobial acid buffering bioadhesive vaginal (ABBV) products having a pH of 4.4 were investigated. Methods: Four groups of female rats were administered 0.1ml sham negative control, ABBV gel, ABBV tablet and suspension of marketed formulation, for 14 consecutive days. Safety and irritability of ABBV products was assessed on the basis of daily observations (behavior, vaginal bleeding or discharge and pharmacotoxic signs), macroscopic mucosal surface (erythema, edema and discharge) and microscopic (inflammation, cell proliferation, edema and flattening of cells) observations. Results: In daily observations uneasiness was noticed for about 20 minutes for the first two days, in formulation treated groups. The reason for uneasiness may be the feeling of fullness of vaginal tube or first experience of grittiness or messiness of product. After the first two days there was no sign of uneasiness and animals behaved normally. There was no discharge, bleeding, erythema or edema. A mild parakeratosis was observed with Infa-V, ABBV tablet and gel treated groups. There was no sign of submucosal edema or inflammation in any group. Minimal irritation (score-1) was observed in formulation treated groups, while the irritability score of sham negative control was zero. Conclusion: ABBV formulations having pH 4.4 were found to be safe and non-irritating.

Background: Tsetse-transmitted trypanosomosis remains a constant drain on the financial resources of African livestock keepers, on the productivity of their livestock and their health. Control involves tackling the parasite by treating livestock with trypanocides, or controlling the vector through insecticide-treated traps or cattle, aerial spraying, ground spraying, the sterile insect technique (SIT) or combinations of these. Recently, the use of antioxidants, immunostimulants or immunomodulatory agents such as vitamins and micronutrients in the management of African trypanosomosis have shown some advantage. Vitamin E is able to optimize and enhance the immune response as well as function as an antioxidant. In view of this, there is the need to study the effect of vitamin E supplementation on anaemia, oxidative stress and immune response of Trypanosoma brucei brucei infected rats. Methods: Thirty (30) adult albino rats divided into 5 groups (A - E) of 6 rats each were used for this study. Groups A, B and C were fed with 50, 100, 200 parts per million (ppm) vitamin E in their feed respectively from day 21 pre-infection till the experiment was terminated. Also, groups A, B, C and D rats were each infected with 1.0 × 106 trypanosomes intraperitoneally. Rats in group E served as the uninfected control. The packed cell volume, hemoglobin concentration, parasitaemia, antibody response to sheep red blood cells (SRBC), lipid peroxidation index and antioxidant enzymes activities were used to assess the supplementation. Results: The supplementation was able to increase the PCV and Hb significantly (P<0.05) by day 21 when compared with not supplemented groups. Following infection on day 21 OTS, there was decrease in PCV with the infected not supplemented group being significantly lower than other groups on day 35 OTS. The supplementation led to significant (P<0.05) increase in antibody response to SRBC and leucocyte count of the supplemented group at pre-infection when compared with the infected not supplemented and not infected not supplemented groups. The infection however led to further increase in the antibody titre and leucocyte count on day 28 OTS followed by decrease from day 35 OTS. The serum MDA concentration of the supplemented groups decreased significantly on day 21 OTS but was reversed by infection on day 42 OTS. The antioxidant enzymes (superoxide dismutase and catalase) activities increased significantly (P<0.05) in the supplemented groups on day 21 OTS but there was a significant (P<0.05) decrease in these enzymes activities following infection. Conclusion: In conclusion, supplementation with vitamin E showed some beneficial effects in the management of trypanosomosis in rats.

Objective: To determine if better antiretroviral (ARV) central nervous system (CNS) penetration is associated with reduced rates of chronic pain in people living with HIV (PLWH). Background: Chronic pain remains prevalent in PLWH despite widespread ARV use. Mechanisms underlying this prevalence remain unknown, though neuroinflammation from persistent CNS HIV infection and maladaptive plastic changes in the CNS have been implicated. Here we hypothesize that better CNS ARV penetration, measured using the CNS Penetration-Effectiveness (CPE) score, would decrease rates of chronic pain. Methods: We interviewed 254 consecutive adults from an HIV clinic in Chiang Mai, Thailand. We collected data on demographics, HIV history, ARV use, and pain characteristics. Patients were evaluated for depression using a Thai two question Patient Health Questionnaire (PHQ-2). Modified CPE score was calculated using established methods and grouped a priori into “low CPE” (≤7, poor penetration) and “high CPE” (≥8, good penetration). CPE score was compared with chronic pain scores in SPSS using appropriate statistical tests. A relationship between CPE score and a positive depression screen was tested further using multivariable binary logistic models. Results: 245 of 254 subjects were on ARVs. Complete ARV data was available for 235 patients. 137 of these 235 patients (58.3%) had a CPE score ≤7, and 98 (41.7%) had a score ≥8. 49 patients had chronic pain, and 9 had neuropathic pain. Low CPE score was not associated with chronic pain (p=0.64), neuropathic pain (p=0.56), or frequent pain (p=0.80), nor was it associated with the severity of reported “worst pain” or “average pain” in the last 24 hours (p=0.18 and 0.48, respectively). Post-hoc analysis revealed that higher CPE score was a significant independent risk factor for depression measured by a positive PHQ-2 screen [OR (95% CI) = 1.29 (1.04-1.61), p=0.02]. This relationship was mediated primarily by exposure to zidovudine. Conclusion: CPE score is not associated with chronic pain in PLWH. Post-hoc analysis demonstrated that CPE score, and zidovudine exposure in particular, predicts a positive depression screen. Given the substantial morbidity associated with chronic pain and mood disorders in PLWH, additional studies to determine preventable and treatable factors are imperative.

Background: Onchocerciasis is one of the neglected tropical diseases with over 37 million persons affected and a risk population of over 120 million. Ivermectin, the only available drug for the treatment of onchocerciasis is microfilaricidal and there is no current drug effective against macrofilariae. The long duration of treatment of this parasite coupled with the emergence of resistance and the occurrence of severe side effects especially in cases of co-infection with Loa loa, necessitate the search for safe and more effective drug leads. Methods: Six isoniazid-derived Schiff bases were synthesized by condensation of isoniazid and various aromatic aldehydes in methanol. The complexes were synthesized in the metal to ligand molar ratio of 1:2. The ligands and the Zn(II) and Cu(II) complexes were characterized by 1H- and 13C-NMR, as well as infrared spectroscopy. Results: From the spectroscopic data, the ligands were found to coordinate to the central metal ions through the carbonyl oxygen atom as well as the azomethine nitrogen atom. The Zn(II) complexes were octahedral while the Cu(II) complexes were tetrahedral. The ligands and their Zn(II) complexes were inactive against microfilaria while the Cu(II) complexes showed significant activity against both micro- and macrofilaria with IC50 values of 5 μg/mL and 10 μg/mL respectively. Conclusion: The Cu(II) complexes are potential targets for the development of more effective anti-onchocercal agents. This is the first report of the anti-onchocercal activity of these isoniazid-derived Schiff bases and their complexes.

Background: Tuberculosis (TB) is the one which remains the world’s greatest public health challenges. Worldwide resurgence of TB is due to two major problems: the AIDS epidemic and the outbreak of multidrug resistant (MDR) TB. Thus, there is an urgent need to develop anti-TB drugs with enhanced activity against MDR strains. In the present study a hybrid pharmacophore based approach was used to design and synthesize Isatin - quinoline hybrids. All the new series of hybrids (5a-j & 6a-l) were investigated for molecular docking study against enoyl ACP reductase enzyme. Methods: The docking study was performed on 22 newly designed isatin analogs on the active site of crystal structure of enoyl-ACP reductase enzyme (PDB ID: 4TZK). The binding modes of these analogs were calculated based on the two parameters such as binding energy and inhibition constant. Isatin- quinoline hybrid molecules were synthesized and characterized by various well known physical and spectral analyses (FT-IR, 1H-NMR and Mass spectroscopy). Results: According to the docking study compound 6h has highest binding affinity with a binding energy of -9.08 kcal/mol and predicted inhibition constant is 221.75 nanomolar. This compound exhibited well established hydrophobic bonds with amino acid Tyr 158 and the co factor NAD 500 in the receptor active pocket and fortunately these two are responsible for the enzyme activity. Further, in vitro antitubercular activity has been performed for all the hybrids against drug resistant strains of Mycobacterium tuberculosis (M.tb) using microdilution assay and their minimum inhibitory concetration (MIC) was determined. Compound 6h has the good inhibitory (0.09 μM) activity as compared to the reference drug, isoniazide (0.03 μM). Conclusion: The enhanced activity of the compound 6h against poly and multi drug resistant strains is due to the presence of electron withdrawing groups on the aromatic ring of isatin.

Background: AIDS continues to be a major public health issue worldwide. In 2014, an estimated 36.9 million people were living with HIV, in the same year, around 1.2 million people died due to AIDS-related illnesses. Due to global efforts particularly made in the last decade has reduced mortality rate due to AIDS and associated diseases. But still many people living with HIV/AIDS particularly in the low and middle income countries do not have access of anti-HIV drugs. Moreover, still there is no permanent cure of disease and rapid emergence of drug resistance by HIV towards the current available therapy further drive the need for the search of new potential anti- HIV drugs. Methods: In the present study, fifteen novel 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-phenylpropanamide derivatives (5a-o) were designed as HIV-1 Reverse Transcriptase (RT) inhibitors, in-silico evaluated for drug likeness behaviour, synthesized and characterized. Compounds were evaluated in-vitro for inhibition of HIV-1 RT activity. Three compounds (5a, 5f and 5o) as representative of the series were evaluated for cytotoxicity studies on human T lymphocytes (C8166 cells). All the synthesized compounds were also evaluated for in-vitro antibacterial (E. coli, P. putida, S. aureus and B. cereus) and antifungal (C. albicans and A. niger) activity. Results: All compounds (5a-o) possessed drug-likeness behavior based upon their in-silico predicted drug-likeness properties. Five compounds 5f, 5h, 5i, 5k and 5n exhibited more than 50% inhibition of HIV-1 RT, in which compound 5h showed highest inhibition (61%). Cytotoxicity studies of compounds 5a, 5f and 5o on T lymphocytes revealed that, all three exhibited CC50 >200 μg/ml. Four compounds 5f, 5i, 5j and 5n showed significant inhibition against the tested G(-) ve (E. coli and P. putida) bacterial strains while one compound 5f significantly inhibited the growth of all tested bacterial strains. Among the series, four compounds (5e, 5f, 5i and 5m) significantly inhibited the growth of A. niger, while compound 5m exhibited significant inhibition of both the tested fungal strains. Conclusion: Titled compounds (5a-o) exhibited weak to significant inhibition of HIV-1 RT, particularly 5h. Four compounds showed significant anti-bacterial activity against the both tested G(-)ve bacterial strains, moreover compound 5f significantly inhibited the growth of all four tested bacterial strains. Four compounds significantly inhibited the growth of A. niger, in which compound 5m exhibited significant inhibition of both the tested fungal strains.