Synthesis and evaluation of 2-phenylamino-1,4-naphthoquinones derivatives as potential hypoglycaemic agents

Abstract Due to the severe side effects revealed by most of the currently used antidiabetic medicines, search for finding new and safe drugs to manage diabetes is continued. Naphthoquinones possessing strong antioxidant properties have been employed as candidates for diabetes therapy. Present study is aimed at finding the antioxidant and hypoglycaemic potential of some novel derivatives of 2-phenylamino-1,4-naphthoquinones (PAN) including chloro, nitro, methyl and bromo (5a-d) derivatives synthesized by single pot experiment. Product crystals were purified by TLC and characterized by FT-IR. The antioxidant potential of the compounds was assayed through DPPH radical scavenging and reducing power activities noted as UV-vis. absorbance. The DPPH assay has showed the powerful antioxidant activity of nitro and bromo derivatives, while the nitro derivative showed the significant reduction potential towards FRAP assay. Hypoglycaemic potential of the compounds was studied in rat animal model. All synthesized compounds revealed better hypoglycaemic activity; however, the chloro-derivative exhibited the more potent hypoglycaemic activity showing about 43% reduction in the mean blood glucose levels of the treated animals. As the bioreduction of naphthoquinones may be influenced by changing its redox properties, it has been noticed that the e-donating resonance effect (+R) of chloro group has shown the significant effects on biological activity through stabalization of its imine form which limits the potential of generation of free radicals during bioreduction of quinones and thus has been proposed as the reason of its hypoglycaemic activity. Future studies employing the properties of e-donating groups of PAN may optimize the drug-receptor interaction for better drug designing and drug development strategies against diabetes and also for the clinical trials.

Resumo Em razão dos graves efeitos colaterais causados pela maioria dos medicamentos antidiabéticos atualmente utilizados, continua a busca por novos medicamentos seguros para o controle do diabetes. As naftoquinonas, que possuem fortes propriedades antioxidantes, têm sido empregadas como candidatas à terapia do diabetes. O presente estudo visa encontrar o potencial antioxidante e hipoglicemiante de alguns novos derivados de 2-fenilamino-1,4-naftoquinonas (PAN), incluindo derivados de cloro, nitro, metil e bromo (5a-d) sintetizados por experimento em pote único. Os cristais do produto foram purificados por TLC e caracterizados por FT-IR. O potencial antioxidante dos compostos foi testado por meio de atividades de sequestro de radicais DPPH e redução de energia observada como absorção no UV-vis. O ensaio DPPH mostrou a poderosa atividade antioxidante dos derivados nitro e bromo, enquanto o derivado nitro mostrou o potencial de redução significativo para o ensaio FRAP. O potencial hipoglicêmico dos compostos foi estudado em modelo animal de rato. Todos os compostos sintetizados revelaram melhor atividade hipoglicemiante; no entanto, o derivado cloro apresentou atividade hipoglicêmica mais potente, com redução de 43% nos níveis médios de glicose no sangue dos animais tratados. Como a biorredução de naftoquinonas pode ser influenciada pela alteração de suas propriedades redox, notou-se que o efeito da doação eletrônica por ressonância (+R) do grupo cloro tem sido significativo na atividade biológica por meio da estabilização de sua forma imina, que limita o potencial de geração de radicais livres durante a biorredução de quinonas, e, portanto, tem sido proposto como a razão de sua atividade hipoglicemiante. Estudos futuros empregando as propriedades de grupos de doação eletrônica de PAN podem otimizar a interação droga-receptor para melhor planejamento de medicamentos e estratégias de desenvolvimento de medicamentos contra o diabetes e também para os ensaios clínicos.

Synthesis and evaluation of 2-phenylamino-1, 4-naphthoquinones derivatives as potential hypoglycaemic agents / Síntese e avaliação de derivados de 2-fenilamino-1, 4-naftoquinonas como potenciais agentes hipoglicemiantes

Due to the severe side effects revealed by most of the currently used antidiabetic medicines, search for finding new and safe drugs to manage diabetes is continued. Naphthoquinones possessing strong antioxidant properties have been employed as candidates for diabetes therapy. Present study is aimed at finding the antioxidant and hypoglycaemic potential of some novel derivatives of 2-phenylamino-1,4-naphthoquinones (PAN) including chloro, nitro, methyl and bromo (5a-d) derivatives synthesized by single pot experiment. Product crystals were purified by TLC and characterized by FT-IR. The antioxidant potential of the compounds was assayed through DPPH radical scavenging and reducing power activities noted as UV-vis. absorbance. The DPPH assay has showed the powerful antioxidant activity of nitro and bromo derivatives, while the nitro derivative showed the significant reduction potential towards FRAP assay. Hypoglycaemic potential of the compounds was studied in rat animal model. All synthesized compounds revealed better hypoglycaemic activity; however, the chloro-derivative exhibited the more potent hypoglycaemic activity showing about 43% reduction in the mean blood glucose levels of the treated animals. As the bioreduction of naphthoquinones may be influenced by changing its redox properties, it has been noticed that the e-donating resonance effect (+R) of 'chloro' group has shown the significant effects on biological activity through stabalization of its imine form which limits the potential of generation of free radicals during bioreduction of quinones and thus has been proposed as the reason of its hypoglycaemic activity. Future studies employing the properties of e-donating groups of PAN may optimize the drug-receptor interaction for better drug designing and drug development strategies against diabetes and also for the clinical trials.

Em razão dos graves efeitos colaterais causados pela maioria dos medicamentos antidiabéticos atualmente utilizados, continua a busca por novos medicamentos seguros para o controle do diabetes. As naftoquinonas, que possuem fortes propriedades antioxidantes, têm sido empregadas como candidatas à terapia do diabetes. O presente estudo visa encontrar o potencial antioxidante e hipoglicemiante de alguns novos derivados de 2-fenilamino-1,4-naftoquinonas (PAN), incluindo derivados de cloro, nitro, metil e bromo (5a-d) sintetizados por experimento em pote único. Os cristais do produto foram purificados por TLC e caracterizados por FT-IR. O potencial antioxidante dos compostos foi testado por meio de atividades de sequestro de radicais DPPH e redução de energia observada como absorção no UV-vis. O ensaio DPPH mostrou a poderosa atividade antioxidante dos derivados nitro e bromo, enquanto o derivado nitro mostrou o potencial de redução significativo para o ensaio FRAP. O potencial hipoglicêmico dos compostos foi estudado em modelo animal de rato. Todos os compostos sintetizados revelaram melhor atividade hipoglicemiante; no entanto, o derivado cloro apresentou atividade hipoglicêmica mais potente, com redução de 43% nos níveis médios de glicose no sangue dos animais tratados. Como a biorredução de naftoquinonas pode ser influenciada pela alteração de suas propriedades redox, notou-se que o efeito da doação eletrônica por ressonância (+R) do grupo "cloro" tem sido significativo na atividade biológica por meio da estabilização de sua forma imina, que limita o potencial de geração de radicais livres durante a biorredução de quinonas, e, portanto, tem sido proposto como a razão de sua atividade hipoglicemiante. Estudos futuros empregando as propriedades de grupos de doação eletrônica de PAN podem otimizar a interação droga-receptor para melhor planejamento de medicamentos e estratégias de desenvolvimento de medicamentos contra o diabetes e também para os ensaios clínicos.

A study on management of type 2 diabetic patients with complications

Background: Diabetes is a major public health problem both in developing and non-developing countries across the world. It is a chronic disease, which in long term causes several complications resulting in poly pharmacy for its management. Hence, this study was determined to analyze the drug utilization pattern for the management of type 2 diabetes with complications.Methods: A prospective, observational and non-interventional study was carried out in 100 diabetic patients with one or other complications admitted in medicine wards at Dhiraj Hospital. Patients who signed informed consent form were only included in the study. All the data were recorded from patients’ case files and analyzed.Results: Result of total 100 patients, maximum number 52 (52%) were falling in group of 61-70 kg and only 2 (2%) in 81-90 kg. Out of 100 diabetic patients, 40 (40%) were managed with insulin in addition to oral antidiabetic agents, 37 (37%) were managed with only Oral Hypoglycemic Agents (OHA) and 23 (23%) were managed with only insulin. The most commonly prescribed oral antidiabetic group of drug was Biguanides in 60 (60%) and most prescribed insulin was short acting Insulin in 40 (40%) patients.Conclusions: The diabetic patients are more prone to cardiovascular and other complications leading to a co morbid condition. The poly pharmacy is likely to occur in diabetic patients suffering with secondary complications. Therefore, intense blood sugar control with proper education can prevent the co morbid state and finally helps in reducing the economic burden.

SECTION A: Pathophysiology of Type 2 Diabetes Mellitus in Children. SECTION B: Clinical scenario of Type 2 Diabetes mellitus in children. SECTION C: Epidemiology and Prevention of Type 2 Diabetes mellitus in children.

SECTION A: Pathophysiology of Type 2 Diabetes mellitus in children Dr. Jyoti Kini While Type 2 diabetes mellitus (T2DM) continues to be a disease of the elderly and the middle aged, currently there has been an upsurge in the incidence of T2DM in the adolescents and the young. Family history, maternal gestational diabetes, low birth weight have contributory role to play in the pathophysiology of T2DM. The pathophysiology underlying the development of alterations in glucose metabolism ranging from abnormal fasting glucose (AFG) to impaired glucose intolerance (IGT) is multifactorial. The early onset of diabetes in childhood or adolescence heralds a long disease interval with resultant escalation of the probability of development of co-morbidities and the entire range of macro- and microvascular complications. SECTION B: Clinical scenario of Type 2 Diabetes mellitus in children Dr. Mallikarjungowda S Patil Type 2 diabetes mellitus (T2DM) is a heterogeneous disorder, characterized by peripheral insulin resistance and failure of beta cells to keep up with increasing insulin demand. T2DM children are usually obese, may present with mild symptoms of polyuria and polydypsia. A systemic approach for treatment of T2DM should be implemented according to the natural course of the disease, including adding insulin when oral hypoglycemic agents failure occurs. Life style modification is an essential part of management. When lifestyle interventions fail to normalize blood glucose, oral hypoglycemic agents are introduced for management of persistent hyperglycemia. SECTION C: Epidemiology and Prevention of Type 2 Diabetes mellitus in children Dr. Savindika Nawarathna , Dr. Animesh Jain Type 2 diabetes mellitus was considered rare amongst children, but recently the incidence has increased worldwide with almost half of the newly diagnosed cases being children and adolescents. Type 2 diabetes mellitus (T2DM) is primarily characterized by insulin resistance detected at the level of skeletal muscle, liver, and adipose tissues with a failure of β-cell compensation and a relative insulin deficiency. A variety of risk factors like race, obesity, insulin resistance, family history, psychococial factors, birth weight, exposure to maternal DM and breastfeeding can influence the development of T2DM. Type 2 DM screening in the paediatric population should be clinically focused and take into account not only those risk factors identified in the American Diabetes Association guidelines, but also the clinical context, pubertal status, and the results of simple screening measures such as fasting glucose and triglycerides. More outcome-based research is required before general screening, to identify children and adolescents with pre-diabetes or insulin resistance can be recommended. The pathophysiology underlying the development of alterations in glucose metabolism ranging from abnormal fasting glucose (AFG) to impaired glucose intolerance (IGT) is multifactorial. The early onset of diabetes in childhood or adolescence heralds a long disease interval with resultant escalation of the probability of development of co-morbidities and the entire range of macro- and microvascular complications.

Efficacy and safety of Tinospora cordifolia (Tc) as an add-on therapy in patients with type-2 diabetes.

Background: Type 2 diabetes has become a global epidemic. Tinospora cordifolia is being used in the treatment of type 2 diabetes since ancient times. It is a common misconception that Ayurvedic medicines are always safe. In fact, they also pose serious health risks either in the form of adverse reactions or in the form of drug interactions. Hence this study was undertaken to study the efficacy and safety of Tc on human subjects. Methods: We recruited 40 type 2 diabetic patients who were on oral hypoglycaemic agents. These patients were then randomly divided into two groups, A and B. Patients in group A continued with their anti-diabetic medications while in group B Tc was given at a dose of 500 mg three times daily along with their conventional medications. The fasting and post prandial blood glucose levels, renal function tests and liver function tests were recorded at baseline, 3 months and 6 months. Results: During the course of study we observed a decrease in the fasting and post prandial blood glucose levels of the patients. No significant change was observed in the renal function tests and liver function tests and no other event of any adverse drug reactions were recorded. Conclusion: Tinospora cordifolia (Tc) is effective as an add-on therapy in patients with type-2 diabetes. There is no negative impact of Tc on the renal as well as liver function tests.

Effect of oral hypoglycaemic agents on bone metabolism in patients with type 2 diabetes mellitus & occurrence of osteoporosis.

Background & objectives: Type 2 diabetes mellitus (T2DM) is considered to be a protective factor against development of osteoporosis. But oral hypoglycaemic agents (OHA) are likely to increase the risk of osteoporosis. This study was carried out to evaluate the effect of various OHA on bone mineral density (BMD) in patients with T2DM. Methods: Forty one patients (study group) with T2DM (mean age 51.9±5.5 yr; 31 females) receiving treatment with oral hypoglycaemic agents (OHA) [thiazolidinediones alone (n=14) or in combination with other OHA (n=27)] for a period of at least three consecutive years and 41 age- and gender-matched healthy controls (mean age 51.4±5.1 yr) were included in the study. A detailed clinical history was taken and all were subjected to physical examination and recording of anthropometric data. BMD was assessed for both patients and controls. Results: The mean body mass index (kg/m2) (26.5±4.90 vs 27.3 ±5.33) and median [inter-quartile range (IQR)] duration of menopause (yr) among women [6(2-12) vs 6(1-13)] were comparable between both groups. The bone mineral density (BMD; g/cm2) at the level of neck of femur (NOF) (0.761±0.112 vs 0.762±0.110), lumbar spine antero-posterior view (LSAP) (0.849±0.127 vs 0.854±0.135); median Z-score NOF {0.100[(-0.850)-(0.550)] vs -0.200[(-0.800)-(0.600)]}, LSAP {-1.200[(-1.700)-(-0.200)] vs -1.300 [(-1.85)-(-0.400)]} were also similar in study and control groups. Presence of normal BMD (9/41 vs 8/41), osteopenia (16/41 vs 18/41) and osteoporosis (16/41 vs 15/41) were comparable between the study and control groups. No significant difference was observed in the BMD, T-scores and Z-scores at NOF and LSAP among T2DM patients treated with thiazolidinediones; those treated with other OHA and controls. Interpretation & conclusions: The present findings show that the use of OHA for a period of three years or more does not significantly affect the BMD in patients with T2DM.

Analysis on the Durg Utilization of Oral Hypoglycaemic Agents in an Inland Hospital and a Coastal Hospital / 药物流行病学杂志

To get information about the status of use of oral hypoglycaemic agents in an inland and coastal hospitals,the ordes of total cost and DDDs were employed to compare the use of oral hypoglycaemic agents in an inland hospital and a coastal hospital.Our results showed that the much less biguanides were used in the coastal hospital as compared with the inland hospital.It is conclinical practice included dimethyl biguanide,glipizide,gliclazide and glibenclamide.