Sunil Menghani

Development of selective DprE1 inhibitors: Design, synthesis, crystal structure and antitubercular activity of benzothiazolylpyrimidine-5-carboxamides

Decaprenylphosphoryl-b-D-ribose 20-epimerase (DprE1) is a potential drug target for development of antitubercular agents. Structure based drug discovery approach yielded twenty novel derivatives of benzothiazolylpyrimidine-5-carboxamides (7a-t) which were synthesised by three component one pot reaction involving benzothiazolyl oxobutanamide, thiourea and substituted aromatic benzaldehydes. These derivatives were evaluated for antitubercular activity to determine MIC and compound 7a, 7e, 7f and 7o were found to be potentially active against Mycobacterium tuberculosis (H37Rv). Log P of these compounds was found to be between 2.0 and 3.0 making them suitable for oral dosing. DprE1 selectivity and pharmacokinetic studies were carried out for these compounds of which 7a and 7o were found to be highly selective and bioavailability was found to be above 52% by oral dose. Crystal structure of 7a was studied and molecular packing was determined, it exhibited a triclinic crystal lattice arrangement having hydrogen bonded dimeric arrangement. Drug receptor interactions were studied which exhibited docking in the active site of receptor with hydrogen bonding, hydrophobic interactions, vdW interactions with amino acid residues such as Cys387, Asn385, Lys418, Tyr314, Gln334 and Lys367 respectively. 3D QSAR analysis was carried out by kNN-MFA method to determine and develop theoretical model, best suitable model was found to be based on Simulated Annealing k-Neariest Neighbour Molecular Field Analysis (SA kNN-MFA). The model provided with hydrophobic descriptors in positive side indicating the need of bulky groups, steric and electronegative descriptors in negative coordinates hints with contribution by the electronegative substitutions as favourable and desirable moieties for enhancing the activity. The q(2), q(2)_se and Pred_r(2)se were found to be 0.5000, 0.6404 and 1.0094 respectively. A pharmacophore model was generated which suggested for necessity of aromatic, aliphatic carbon centre and hydrogen bond donor for development of newer DprE1 selective inhibitors.

Chandipura Virus: an emerging tropical pathogen.

Chandipura Virus (CHPV), a member of Rhabdoviridae, is responsible for an explosive outbreak in rural areas of India. It affects mostly children and is characterized by influenza-like illness and neurologic dysfunctions. It is transmitted by vectors such as mosquitoes, ticks and sand flies. An effective real-time one step reverse-transcriptase PCR assay method is adopted for diagnosis of this virus. CHPV has a negative sense RNA genome encoding five different proteins (N, P, M, G, and L). P protein plays a vital role in the viruss life cycle, while M protein is lethal in nature. There is no specific treatment available to date, symptomatic treatment involves use of mannitol to reduce brain edema. A Vero cell based vaccine candidate against CHPV was evaluated efficiently as a preventive agent against it. Prevention is the best method to suppress CHPV infection. Containment of disease transmitting vectors, maintaining good nutrition, health, hygiene and awareness in rural areas will help in curbing the menace of CHPV. Thus, to control virus transmission some immense preventive measures need to be attempted until a good anti-CHPV agent is developed.

Development of dual inhibitors targeting DprE1 and AHAS for treatment of Mycobacterium tuberculosis infection

Background The emerging multidrug resistant (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis (MTB) infection is increasing with greater complexity, estimated 220000-400000 tuberculosis cases emerged in 2011 globally. A number of lead compounds have been developed for treatment of MDR and XDR TB, but no new chemical entity has emerged for clinical use. Recently DprE1 and AHAS have been identified as promising drug targets.

Progress in Synthesis of Monoglycerides for Use in Food and Pharmaceuticals

Glycerides are lipid esters of the glycerol molecule and fatty acids. Their primary function is the storage of energy. Due to its structure and properties, glycerol participates in the formulation or synthesis of many compounds such as food products, cosmetics, pharmaceuticals, liquid detergents. Monoglycerides (MGs) can be formed by both industrial chemical glycerolysis and biological or enzymatic processes. Chemical glycerolysis bring issues of low MGs yield, high operating temperature, formation of undesirable by-products and high energy consumption. On the other hand enzymatic processes have advantages of mild reaction conditions and high purity of MGs. But, several purification steps are required to obtain food or pharmaceutical grade MG, such as neutralization of the reaction media and discoloration followed by expensive molecular distillation. The purpose of this article is to review the main challenges in the synthesis of MGs from triglycerides (TGs) contained in the various fixed oils and application thereof in the food and pharmaceuticals.

LEDGF/p75 IN interaction inhibitors: in silico studies of an old target with novel approach

Background Despite development in Anti Retroviral Therapy (ART), reports of HIV infection remains in continuous momentum and a cure seems to be imaginary. Raltegravir, an Integrase (IN) inhibitor, provides some life expectancy to patients on salvage therapy. Nowadays, IN inhibitors reported with resistance and shows cross resistance to other drugs in this class. Human Lens Epithelium Derived Growth Factor (LEDGF)/p75 plays a vital role in the HIV life cycle and its importance has been shown in numerous studies. In the LEDGF/p75 IN complex, LEDGF binds to IN at a region other than the catalytic active site. Thus, we tried computationally to approach these IN-LEDGF interaction sites as a novel target in therapy.

Smallest Organism; Highest Threat -

Ever since the discovery of virus in beginning of 20th century, infections caused by these organisms have captured attention of researchers. The evolution of viruses is still a controversy, even same for their categorization in either living or non-living. It is clear that besides many controversies virus remains challenging to treat as well as to control in some extent. Though vaccines are available as prophylactic tool and antiviral drugs for treatment, still virus exist in host cells if they successfully invade biological machinery. Now it remains as challenge to treat these smallest organisms with high degree of efficacy and safety. To answer the demand of the present world there is urgent need of more potent and novel drugs for treatment and vaccines to prevent infection. Answer to this problem will definitely reduce casualties occurring worldwide. This review presents few of the pandemics, their causative agents, current status of treatment and future prospective.