Importance of cytochromes in cyclization reactions: Quantum chemical study on a model reaction of proguanil to cycloguanil

Proguanil, an anti‐malarial prodrug, undergoes cytochrome P450 catalyzed biotransformation to the pharmacologically active triazine metabolite (cycloguanil), which inhibits plasmodial dihydrofolate reductase. This cyclization is catalyzed by CYP2C19 and many anti‐malarial lead compounds are being designed and synthesized to exploit this pathway. Quantum chemical calculations were performed using the model species (Cpd I for active species of cytochrome and N4‐isopropyl‐N6‐methylbiguanide for proguanil) to elucidate the mechanism of the cyclization pathway. The overall reaction involves the loss of a water molecule, and is exothermic by approximately 55 kcal/mol, and involves a barrier of approximately 17 kcal/mol. The plausible reaction pathway involves the initial H‐radical abstraction from the isopropyl group by Cpd I, followed by two alternative paths‐ (i) oxygen rebound to provide hydroxyl derivative and (ii) loss of additional H‐radical to yield 1,3,5‐triazatriene, which undergoes cyclization. This study helped in understanding the role of the active species of cytochromes in this important cyclization reaction. © 2014 Wiley Periodicals, Inc.     

An epidemiological study of low back pain in professional drivers

The prevalence of low back pain (LBP) was investigated in 598 Italian professional drivers exposed to whole-body vibration (WBV) and ergonomic risk factors (drivers of earth moving machines, fork-lift truck drivers, truck drivers, bus drivers). The control group consisted of a small sample of 30 fire inspectors not exposed to WBV. Personal, occupational and health histories were collected by means of a structured questionnaire. Vibration measurements were performed on representative samples of the machines and vehicles used by the driver groups. From the vibration magnitudes and exposure durations, alternative measures of vibration dose were estimated for each subject. Daily vibration exposure, expressed in terms of 8-h energy-equivalent frequency-weighted acceleration, A(8), averaged 0.28-0.61 (range 0.10-1.18) m s⁻² rms in the driver groups. Duration of exposure to WBV ranged between 1 and 41 years. The 7-day and 12-month prevalence of LBP was greater in the driver groups than in the controls. In the professional drivers, the occurrence of 12-month LBP, high intensity of LBP (Von Korff pain scale score ?5), and LBP disability (Roland & Morris disability scale score ?12) significantly increased with increasing cumulative vibration exposure. Even though several alternative measures of vibration exposure were associated with LBP outcomes, nevertheless a more regular trend of association with LBP was found for vibration dose expressed as ∑a_vit_i (m s⁻² h), in which the frequency-weighted acceleration, a_v, and lifetime exposure duration, t, were given equal weight. In multivariate data analysis, individual characteristics (e.g. age, body mass index) and a physical load index (derived from combining manual materials handling and awkward postures) were significantly associated with LBP outcomes, while psychosocial work factors (e.g. job decision, job support) showed a marginal relation to LBP. This study tends to confirm that professional driving in industry is associated with an increased risk of work-related LBP. Exposure to WBV and physical loading factors at work are important components of the multifactorial origin of LBP in professional drivers.     

Electronic structure and conformational analysis of P218: An antimalarial drug candidate

P218 is one of the very important and recent lead compounds for antimalarial research. The 3D structural and electronic details of P218 are not available. In this article, quantum chemical studies to understand the possible 3D structures of P218 are reported and compared with 3D structures from the active site cavities of hDHFR and PfDHFR. The neutral P218, can adopt open chain as well as cyclic arrangements. Under implicit solvent condition a zwitterionic‐cyclic conformer is found to be quite possible. Microsolvation studies using explicit water molecules indicate that one water molecule may bridge the two ends of zwitterionic‐cyclic P218. It was observed that the protonation occurs preferentially at N¹ position of the 2,4‐diaminopyrimidine ring, with a proton affinity of 274.49 kcal/mol (implicit solvent phase) and 236.35 kcal/mol (gas phase). A dimer of P218 may be zwitterionic dimer, the dimer formation can release upto ～28.60 kcal/mol (implicit solvent phase).