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The growth of industry, especially pharmaceutical industry, calls for intensive and innovative research. The chapter attempts to capture these in the growth of Indian Pharma over the years beginning from Acharya’s foray in 1901 and traces the entry of Indian and multinational companies into manufacturing activities, the latter hedged by protective measures like MRTP ACT and Patent ACT of 1970. Sales turnovers were modest but a small number of Indian companies and even a very few multinationals started new drug discovery research (NDDR). The Government on the other hand, as a measure of self-sufficiency, built national institutions like Central Drug Research Institute with multidisciplinary facilities for NDDR and process development of drugs. In the meantime, Indian Pharma grew strongly under the umbrella of the Indian Patent Act 1970 and established itself as suppliers of affordable generics of quality medicines. The Hatch-Waxman Act 1984 of the USA leading to the promise of obtaining approval for abbreviated new drug applications (ANDA) opened the gates for the lucrative US generics market which India was well set to exploit with its established skills in manufacture of APIs and formulations. Many Indian companies now had the means to venture into NDDR which became a necessity following the implementation of product patent regime since 2005.

Introduction FXS is the leading cause of intellectual disabilities in males and a major monogenic cause of ASD (Autism spectrum disorders). It occurs due to the loss of FMRP, whose role in early development is not well understood. In this study, we have used a novel DNAzyme based approach to create a larval model of FXS in zebrafish with specific focus on the early developmental window. Methods Fmr1specific DNAzymes were electroporated into embryos to create the knockdown. Changes in RNA and protein levels of FMRP and relevant biomarkers were measured in the 0-7dpf window. Behavioral tests to measure anxiety, cognitive impairments and irritability in the larvae were conducted at the 7dpf stage. Drug treatment was carried out at various time points in the 0-7dpf window to identify the critical window for pharmacological intervention. Results The DNAzyme based knockdown approach led to a significant knockdown of FMRP in the zebrafish embryos, accompanied by increased anxiety, irritability and cognitive impairments at 7dpf, thus creating a robust larval model of FXS. Treatment with the Mavoglurant was able to rescue the behavioral phenotypes in the FXS larvae, and found to be more efficacious in the 0-3dpf window. Discussion The results from this study have revealed that a) a DNAzyme based knockdown approach can be used to create robust larval zebrafish model of disease, in a high-throughput manner and b) optimal window for therapeutic intervention for FXS as well as other pediatric diseases with a monogenic cause can be identified using such a model.

Andrographolide 1, the cytotoxic agent of the plant Andrographis paniculata was subjected to semi-synthetic studies leading to the preparation of a number of potent and novel analogues. Of the analogues synthesized, while 8,17-epoxy andrographolide 6 retained the cytotoxic activity of 1, ester derivatives of 6 exhibited considerable improvement in activity. Lower activity was observed when the epoxy moiety in the triacetate 9, derived from 6 was modified. Synthesis and structure-activity relationships are discussed.

New styryl sulfone compounds have been synthesized and evaluated for their anti-proliferative activity. Among the compounds synthesized, one compound ( 7k ) has shown 51% tumor growth inhibition in mice implanted with HT-29 human carcinoma at 400 mg kg −1 orally.

New 3-O-substituted benzyl pyridazinone compounds have been synthesised and evaluated for their cyclooxygenase inhibitory activity and COX-2 selectivity. Among the compounds synthesised, three compounds (11b–11d) have shown in vitro COX-2 selectivity. These compounds have been evaluated for their in vivo potential using carrageenan-induced rat paw edema assay. One compound (11b) showed 32% anti-inflammatory activity at 30 mg kg−1 dose.

Analogs of 1,5-diarylpyrazoles with a novel pharmacophore at N1 were designed, synthesized and evaluated for the in-vitro cyclooxygenase (COX-1/COX-2) inhibitory activity. The variations at/around position-4 of the C-5 phenyl ring in conjunction with a CF3 and CHF2 groups at C-3 exhibited a high degree of potency and selectivity index (SI) for COX-2 inhibition. The in-vivo evaluation of these potent compounds with a few earlier ones indicated the 4-OMe-phenyl analog 6 and the 4-NHMe-phenyl analog 9 with a CF3, and the 4-OEt-phenyl analog 19 with a CHF2 group at C-3 to possess superior potency than celecoxib. In addition to its impressive anti-inflammatory, antipyretic, analgesic and anti-arthritic properties, compound 6 (DRF-4367) was found to possess an excellent pharmacokinetic profile, gastrointestinal (GI) safety in the long-term arthritis study and COX-2 potency in human whole blood assay. Thus, compound 6 was selected as an orally active anti-inflammatory candidate for pre-clinical evaluation.