Open Access Repository of Indian Theses

Shyam, Shiv

Summary 
 
 226 
SUMMARY 
 
A brief description of the chapters of the thesis entitled “Design and Synthesis of N, 
O & S Containing Heterocyclic Molecular Hybrids as Biodynamic Agents” is 
described below: 
The thesis has been divided in to four chapters 
Chapter 1:  Synthesis and Antimalarial Activity Evaluation of N-Substituted 4-
Aminoquinoline-Pyrimidine Hybrids. 
Chapter 2:  Synthesis and Anti-Tubercular Activity of Imidazo[1,2-a]pyridine-
Triazole and Imidazo[1,2-a]pyridine-Amidoether Hybrids. 
Chapter 3:  Synthesis of Imidazopyridine-Oxadiazole Molecular Hybrids as Anti-
Tubercular Agents. 
Chapter 4:  Synthesis of Substituted Benzothiazole Hydrazono-Amidoether Hybrids 
as Anti-Tubercular Agents. 
. 
 
 
 
 
Summary 
 
 227 
CHAPTER 1 
Synthesis and Antimalarial Activity Evaluation of N-Substituted  
4-Aminoquinoline-Pyrimidine Hybrids 
 
Malaria a life threatening disease, caused by bite of a Plasmodium parasite infected 
female anopheles mosquito, is still a major public health challenge inspired of 
continuous drug discovery. Tropical and subtropical climate region are majorly 
affected areas by malaria, where the parasite can sustain easily. According to WHO 
world Malaria report 2017, there is an estimated (or 445 thousand) deaths in 2016 
globally compared to 446 thousand death in 2015, caused by malaria. African region 
was the extensively affected area with 91% of global malarial deaths followed by 
South-East Asia region for 6% according to WHO 2016. Fifteen countries which 
contributed for 80% of global malaria deaths in 2016 were of sub-Saharan Africa 
Region, except for India. In comparison to 2010, all regions recorded reductions in 
mortality in 2016, except for Eastern Mediterranean Region, where mortality rates 
remained unchanged during this period. The largest decline was observed in South-
East Asia (44%), Africa (37%) and the America (27%). However, between 2015 and 
2016, mortality rates remained intact in South-East Asia, Western Pacific area and 
Africa, while it increased in the Eastern Mediterranean region and America. 
Amongst the five malaria causing plasmodial species viz., P. falciparum, P.ovale, P. 
vivax, P.malariae and P.knowlesi, P. falciparum is the most common and virulent, 
responsible for more than 90% malarial deaths. To overcome the problem of drug-
resistance, several efforts have been made previously including the use of 
combination therapy, development of analogs of the existing drugs as well as the 
incorporation of drug resistance reversers. The concept of ‘hybrid’ drug was put 
Summary 
 
 228 
forward in which two or more pharmacophores are covalently hybridized in an 
anticipation that such molecules will concurrently act on the parent targets and show 
better efficacy and pharmacokinetics than the combination of drugs. Our research 
group has successfully implemented this concept and developed rational molecular 
hybrids as anticancer, antimicrobial and antimalarial agents and demonstrated that 
the molecular hybridization approach can lead to the identification of highly potent 
molecules. In order to study the effect of structural modifications at the linker chain 
of the 4-aminoquinoline-pyrimidine hybrids on their pharmacokinetic behavior and 
antimalarial activity, we thought to substitute the terminal free -NH of diamine linker 
with appropriate aryl/hetero-aryl functionality through a simple reductive amination 
strategy with an appropriate aldehyde. On literature survey, it was found that the 
furan moiety is a part of various antimalarial agents and this scaffold was also known 
to enhance the antimalarial activity and pharmacokinetic behaviour, when present in 
conjunction with 4-aminoquinolines through appropriate spacers. Furthermore, 
assimilation of an intramolecular hydrogen-bonding moiety in the side chain of 4-
aminoquinolines has been proposed to improve the antimalarial activity.  Hence, with 
these perspectives, furan moiety was introduced in the form of furfuryl group in the 
aminoquinoline-pyrimidine hybrids (Scheme 1.1). 
In the present study, we report the synthesis, antiplasmodial activity and cytotoxicity 
of 4-aminoquinoline-furfuryl-pyrimidine and 4-aminoquinoline-pyridin-pyrimidine 
hybrids. In addition, heme binding studies and molecular docking with the reported 
crystal structure of Pf-DHFR-TS were performed to determine their possible mode of 
action. Also, ADME properties of the best active compounds were predicted to assess 
the pharmacokinetic behaviour of the synthesized hybrids.  
Summary 
 
 229 
Antiplasmodial activity evaluation of 4-aminoquinoline-furfuryl-pyrimidine hybrids 
The antimalarial activity was determined by measuring plasmodial LDH activity as 
described in the literature. All the synthesized hybrids were evaluated for the in vitro 
antimalarial activity against CQ-sensitive (D6 clone) and CQ-resistant (W2 clone) 
strains of P. falciparum using choroquine and artemisinin as reference drugs. 
 
Scheme 1.1: Reaction conditions: (a) Neat, 110–120 
o
C, 5 h, 88–90%; (b) MeOH, RT, 12-16 
h, 80-85%; (c) MeOH, NaBH4, RT, 5-6 h, 85-88%; (d) Triethylamine, THF, 60 
o
C, 12 h, 70-
80%; (e) Secondary amines, DMF,  K2CO3, 120 
o
C, 10-12h, 55-86%. 
 
Most of the hybrids showed potent antimalarial activity against both the strains of P. 
falciparum. Out of twenty four synthesized compounds, ten compounds (7a, 7b, 7f, 
7i, 7j, 8a, 8b, 8d, 8e, 8j) with IC50 values ranging from 0.038–0.044 µM, displayed 
better activity than artemisinin (IC50 = 0.045 µM), when tested against CQ-sensitive 
(D6 clone) strain of P. falciparum. While all the compounds except compounds 5b 
and 6b exhibited better activity (IC50 values ranging from 0.039–0.257 µM) than CQ 
Summary 
 
 230 
(IC50 = 0.317 µM) when tested against CQ-resistant (W2 clone) strain of P. 
falciparum. For a particular amine substituted 4-aminoquinoine-pyrimidine hybrids, 
the structure activity relationship (SAR) study demonstrated no obvious trend of 
activity with increasing or decreasing carbon chain from C2 to C3 but changing the 
amino groups for a particular carbon chain length, C2 (7a-7e and 8a-8e), C3 (7f-7j 
and 8f-8j), changes the activity significantly. In general, compounds having methyl or 
ethyl piperazines moieties at the pyrimidine nucleus (7a, 7b, 7h, 7j, 8a, 8b, 8h, 8j) 
were found to be more active than their morpholine, pyrrolidine and piperidine 
counterparts. The two sets of regio-isomers (hybrids 7a–7j vs. 8a–8j) exhibited 
almost similar activity against both the strains of P. falciparum which indicate that the 
point of attachment of pyrimidine nucleus to 4-aminoquinoline nucleus via a carbon 
chain linker may not have a great impact on determining the antimalarial activity 
pattern. Most of the compounds showed good values of resistance index (RI), the ratio 
of the IC50 value against the CQ-resistant strain to the IC50 value against the CQ-
sensitive strain. The low value of resistance index indicates the activity of a 
compound regardless of the susceptibility of the parasite strain, whereas the large 
value indicates the loss of activity due to the drug resistance. Thus a drug molecule 
should have a smaller resistance index. In the present study, resistance index for 
chloroquine was found to be 28.81, whereas tested compounds have RI values in the 
range from 0.775 to 5.58 as show. In fact some compounds such as 7a, 7b, 7h, 7j, 8a, 
8h and 8j have resistance index value near to one suggesting that these molecular 
hybrids are highly effective against P. falciparum strains resistant to parent 
antimalarial drugs such as chloroquine. Cytotoxicity was also determined against 
Vero cell lines. All the compounds showed no toxicity upto 10 µM, the highest 
Summary 
 
 231 
concentration tested, which is very high as compared to their concentrations (IC50) 
responsible for their antimalarial activity. 
Pyridin ring is also present in many antimalarial compounds and these compounds 
show potent antimalarial activity. In order to study the effect of -NH functionalization 
on aminoquinoline-pyrimidine hybrids, 2-substituted pyridin ring was also introduced 
to the hybrids as discussed as discussed in previous section (Scheme 1.2). 
 
Scheme 1.2: Reaction conditions: (a) Neat, 110–120 
o
C, 5 h, 75–85%; (b) MeOH, RT, 12-16 
h, 80-85%; (c) MeOH, NaBH4, RT, 5-6 h, 85-88%; (d) Triethylamine, THF, 60 
o
C, 12 h, 70-
80%; (e) Secondary amines, DMF,  K2CO3, 120 
o
C, 10-12h, 55-86%. 
 
Antiplasmodial activity evaluation of 4-aminoquinoline-pyridin-pyrimidine hybrids 
The antimalarial activity results indicated that all the compounds displayed potent 
antimalarial activity with IC50 values in the range 0.027-1.661 µM against CQ-sensitive 
(D6) strain and IC50 values in the range 0.039-1.443 µM against CQ-resistant (W2) 
strain of P. falciparum. Compound 13d was found to be active against D6 strain of P. 
falciparum with IC50 value 0.027 µM and selectivity index >351. Out of all compounds, 
Summary 
 
 232 
13 compounds (11b, 13b, 13d, 13e, 13g, 13i, 13j, 14c-e, 14g-i,) showed better activity 
than CQ against W2 strain. When the activity of these compounds was compared with 
artemisinin (ART), compounds 13d showed comparable activity to ART & CQ against 
D6 sensitive strain & resistant (W2) strain. The regio-isomeric intermediates, 11a and 
12a containing ethylene diamine linker showed better activity against the sensitive 
strain (IC50 = 0.233 µM & 0.369 µM respectively) as compared to activity against 
resistant strain. In case of regio-isomeric intermediates 11b and 12b, containing three 
carbons linker exhibited better antimalarial activity against resistant strains as compared 
to the activity against the sensitive strain, Interestingly, when the chlorine atoms of the 
regio-isomers 11a and 12a were replaced by various cyclic amines, the activity of all 
the resulting aminoquinoline-pyridin-pyrimidine (13a-13e and 14a-14e) hybrids against 
both sensitive and resistant strains got improved with the exception of two compounds, 
13e and 14a which showed little decline in the activity against the resistant strain. 
Similarly compounds 13f-13j and 14f-14i showed improved activity as compared to 
their corresponding intermediate regio-isomers 11b and 12b against both the strains 
with the exception of three compounds 13f, 13h and 14f which displayed weaker 
activity against CQ-resistant strain than their corresponding intermediates.  
On comparing the effect of cyclic amino substitution on the antimalarial activity, it was 
observed that the compounds in which -Cl group was replaced with 4-methyl piperazine 
(13d, 14d) and 4-ethyl piperazine (13e, 14e) were found to show better activity than the 
compounds in which -Cl group was replaced with piperidine (13a, 14a), pyrrolidine (13b, 
14b) and morpholine (13c, 14c) moieties. No obvious trend of antimalarial activity was 
found on comparison of the activity of regio-isomeric intermediates (11a, 11b, and 12a, 
12b) and their derivatives (13a-13j, 14a-14i), differing in the point of attachment with 
pyrimidine ring. Compounds with ethylene diamine linker (13a-13e and 14a-14d) were 
Summary 
 
 233 
found to be more active than the compounds with propylene diamine linker (13f-13j and 
14f-14i) against CQ-sensitive strains, whereas no particular trend was observed when 
compared activity against the resistant strain. Cytotoxicity was also determined against 
VERO cell lines. All the compounds except 12a, compounds were found to be non-
cytotoxic upto 10 μM, that is too high as compared to their corresponding IC50 values. 
 
CHAPTER 2 
Synthesis and Anti-Tubercular Activity of Imidazo[1,2-a]pyridine-Triazole 
and Imidazo[1,2-a]pyridine-Amidoether Hybrids 
 
Tuberculosis (TB), a leading infectious airborne disease commonly caused by 
Mycobacterium tuberculosis, which belongs to class Mycobacterium, different   strains of 
mycobacteria that cause tuberculosis are M. bovis, M. africanum, M. microti, M. avium 
and M. leprae.
  
In 1882, the German specialist Robert Koch was the primary 
microbiologist to report the effective disengagement of the causative specialist of 
Mycobacterium tuberculosis, who later got Nobel Prize for this disclosure in 1905. Albeit 
basically an aspiratory pathogen, M. tuberculosis can cause disease all through the body. 
In addition, TB has a dynamic spectrum of symptoms, ranging from asymptomatic 
disease to causing severe affects to lungs (pulmonary tuberculosis). Further, TB can 
likewise contaminate other parts of the body (additional pulmonary tuberculosis) for 
example, bones, stomach, brain, skin, digestive tract, spinal cord, lymph nodes, central 
nervous system (CNS), urogenital system. Extra-Pulmonary tuberculosis establishes 15-
20% of all the dynamic instances of tuberculosis. People suffering from dynamic 
aspiratory tuberculosis generally spit, sneeze or cough. Immediately after infecting by 
Mycobacterium tuberculosis, patient does not show any observable symptoms and this 
stage is known as latent tuberculosis. About 10% of the people infected with inactive 
tuberculosis pollutions fall sick and develop symptoms due to less immunity. The side 
Summary 
 
 234 
effect of tuberculosis includes a chronic cough with blood tinged sputum, chest pain, 
fever, night sweats, and weight decrease. The number of individuals infected with TB and 
the deaths detailed each year is immensely high. As indicated by the World Health 
Organization (WHO) worldwide report 2018, TB has caused around 6.4 million new 
cases and among them 1.3 million deaths were observed in HIV-negative people and 
3,00,000 extra deaths from TB among HIV-positive people were observed in 2017. The 
best estimate is that 10 million people created TB disease, 5.8 million men, 3.2 million 
ladies, and 1.0 million kids. The first-line anti-TB drugs such as isoniazid (INH), 
ethambutol (EMB), rifampicin (RIF) and pyrazinamide (PZA) have lost their relevance 
due to the development of MDR, XDR and TDR TB infections more recently. The 
currently available TB treatment regimens have long-term therapy duration (6-12 months) 
and often results in poor patient compliance. Moreover, the increasing cases of drug-
resistant TB (DR-TB), multidrug-resistant TB (MDR-TB, resistant to at least two front-
line drugs such as RIF and INH), extensively drug resistant TB (XDR-TB) and the 
recently cases of totally drug-resistant (TDR) towards currently accessible standard drugs 
has worsen the situation in recent decades. On the other hand, the second-line anti-TB 
drugs such as PAS, cycloserine, amikacin, ethionamide and capreomycin are less 
effective and more toxic. Therefore, To tackle the problem of drug-resistant TB, many 
researchers are now shifting from single-enzyme approach towards whole cell phenotypic 
High Throughput Screening (HTS) approach and recently, imidazo[1,2-a] pyridine is 
identified as a potent anti-tubercular agent against both replicating Mtb H37Rv and multi- 
and extensively drug-resistant (XDR) Mtb strains.
5-9 
The initial HTS hit (1)
5
 has been 
suitably modified by various research groups. These efforts led to the identification of 
pre-clinical anti-TB candidate Q203 Mode of action studies conducted on the 
imidazo[1,2-a]pyridines have revealed that these compounds act as inhibitors of MTb 
Summary 
 
 235 
glutamine synthetase, MTb pantothenate synthetase and of  subunit of the cytochrome 
bc1 complex encoded by the gene qcrB. So we combined biologically active triazole, 
amidoether with imidazo [1,2-a]pyridine etc. play an important role in the development of 
new anti-tubercular agents. Many scientists around the globe have been working on these 
compounds for their possible use as anti-TB agents. We designed a new set of 
imidazo[1,2-a]pyridine-triazole and imidazo[1,2-a]pyridine-imidoether hybrids as anti-
TB agents (Scheme 2.1 and 2.2 respectively). 
 
Scheme 2.1: Reaction conditions: (a) Et2O, NBS, NH4OAc, RT, 6 h, 95%; (b) EtOH, Reflux, 
12 h, 60-65%; (c) EtOH/H2O (3:1 v/v), RT, 12 h, (45-50%); (d) DMF, EDC-HCl, HOBt, NEt3, 
60 
o
C, 2-4 h, 80-85%; (e) DMF,  K2CO3, RT, 12 h, 55-60%;  (f) K2CO3, NaN3, DMF, 50 
o
C, 4-
5 h, 80-90%; (g) DMF, CuSO4.5H2O, Sodium L-ascorbate, 60 C, 12h, 45-56%;  
Summary 
 
 236 
 
Scheme 2.2: Reaction conditions: (a) K2CO3, KI, RT, 10-15h, 55-70%; (b) Et3N, DCM, 0 
o
C, 6-
10 h, 70-90% 
 
Anti-TB activity of imidazo[1,2-a]pyridine-triazole and imidazo[1,2-a]pyridine-
imidoether hybrids 
All the synthesized compounds were screened for their in-vitro antimycobacterial 
activity against Mtb H37Rv strain and isoniazid was used as the reference drug. 
Most of the compounds showed minimum inhibitory concentration (MIC99) above 
50 µM. 
 
Summary 
 
 237 
CHAPTER 3 
Synthesis of Imidazopyridine-Oxadiazole Molecular Hybrids as  
Anti-Tubercular Agents 
 
In this chapter, imidazopyridine-oxadiazole molecular hybrids derivatives were 
designed as possible anti-tubercular agents. This design was based on the literature 
procedures that propose fictionalization of imidazopyridine-oxadiazole (Scheme 3.1). 
 
 
Scheme 3.1: Reaction conditions: (a) Et2O, NBS, NH4OAc, RT, 6 h, 95%; (b) EtOH, Reflux, 
12 h, 65-70%; (c) NH2NH2.H2O, EtOH, Reflux, 12 h, 49-55%; (d) EtOH, CS2/KOH,  0 
o
C, 3h, 
62-65%; (e) EtOH, Reflux, 12 h, 71-74%; (f) Na2CO3, R
1
Br, THF, RT, 12 h, 39-64%. 
Summary 
 
 238 
Anti-TB activity of imidazopyridine-oxadiazole molecular hybrids 
All the synthesized compounds were screened against H37Rv strains. These compounds 
were grouped in three different categories (35a-35t, 36a-36t and 37a-37s) based on 
substitution at C-6 position of imidazo[1,2-a]pyridine. First group 35a-35t has Br at C-
6 position, while second group 36a-36t and third group 37a-37s has chlorine and 
methyl group respectively at C-6 position of imidazo[1,2-a]pyridine. Among all the 
tested compounds most of the compounds were found to be inactive up to 50 M 
concentration except compounds 35n-35q (MIC99 = 3.12-12.5 M), 36o-36q (MIC99 = 
12.5 M) and 37m-37q (MIC99 = 12.5-50 M). 
 
CHAPTER 4 
Synthesis of Substituted Benzothiazole Hydrazono-Amidoether  
Hybrids as Anti-Tubercular Agents 
 
In this chapter, Substituted benzothiazole hydrazono-amidoether derivatives were 
designed as possible anti-tubercular agents. This design was based on the literature 
procedures that propose functionalization of benzothiazole hydrazono-amidoether 
hybrids (Scheme 4.1). 
 
Summary 
 
 239 
 
Scheme 4.1: Reaction conditions: (a) Ethylene glycol, NH2NH2.H2O, HCl, Reflux 6-8h, 85%; 
(b) DCM, K2CO3, RT, 6h, 85-90%; (c) Acetone, K2CO3, KI, RT, 10-12h, 80-85%; (d) EtOH, 60 
o
C, 10-12 h, 60-70%. 
 
Anti-TB activity of substituted benzothiazole hydrazono-amidoether derivatives 
In vitro anti-TB activity of Substituted Benzothiazole Hydrazono-Amidoether 
derivatives is under evaluation. 


English

DESIGN AND SYNTHESIS OF N, O & S CONTAINING HETEROCYCLIC MOLECULAR HYBRIDS AS BIODYNAMIC AGENTS

Chopra, Geetanjali

128 
CHAPTER 6 
Summary and Conclusions 
 
The brief summary and following conclusions can be drawn from this work that, the 
tested plant materials (Eichhornia crassipes, Plumbago capensis and Piper betle) still 
have new antifeedant/ toxic compounds. Moreover the bioactive compounds isolated 
from these plants were easily conjugated with silica nano particles to prepare effective 
formulations. The prepared nanoformulations are successful in exhibiting improved shelf 
life and higher controlled release profile isolated compounds. In addition nano-
formulations also enhance the antifeedant activity of the individual isolated compounds 
against Spdoptera litura F., Achaea janata L. and Helicoverpa armigera H.  
 
 There have been many methods employed to isolate the principle bioactive 
compounds form water hyacinth which eventually yielded a single potent antifeedant 
and toxic compound, 2-propyl piperidine (coniine). I have discovered the occurrence 
of this chemical in water hyacinth plant for the first time and also its insect 
controlling activity/ use in pest control on agricultural crops for the first time. A 
patent was filed on isolation of an active insecticidal compound, 2-propylpiperidine 
(coniine) from aquatic weed water hyacinth, Eichhornia crassipes (Mart.). More 
particularly, the compound can be used as a total insect-controlling agent (Toxicant, 
antifeedant and growth regulator) for pest management in agricultural fields. The 
compound 2-propylpiperidine can be used as a substitute for chemical pesticides or as 
a supplement to chemical pesticides to reduce the usage of synthetic pesticide 
concentrations to protect the environment.   
 
 Different isolations techniques and the purification methods lead to isolate an 
antifeedant compound from the P. capensis. The extensive spectroscopic analysis 
confirmed the compounds as plumbagin. The antifeedant activity of the plumbagin 
was enhanced to more than 10 folds on formulating with silica nanoparticles. 
Moreover the nano nature of formulation has an advantage of distributing the active 
compound on the leaf which enhances the bioavailability of the compound.    
129 
 
 Bioactivity guided fractionation of Piper betle L. yielded two bioactive fractions 
which on fractionation yielded total 8 bioactive compounds. After various chemical 
analysis such as, NMR, FTIR, EIMS, UV-VIS and HPLC, the isolated compounds 
were confirmed as Eugenol, α- pinene, Linalool, Limonene, Trans-caryophyllene, 
Nerolidol, Carene and Ocimene. The results reveal that the Eugenol was obtained in 
higher quantities from P. betle. However the rest of the compounds miner 
constituents of the plants and their quantity isolated from was little and are procured 
from Sigma-Aldrich to prepare the formulation and further investigations.   
 
 The isolated compounds were conjugated with silica nanoparticles to increase its 
shelf life, controlled release properties as well as the bio-activity against major 
agricultural pests. All the formulations prepared showed high stability with higher 
zeta potential, controlled release property as well as enhanced shelf life of the isolated 
botanicals. The added advantage of these formulations is their ability to enhance the 
bioactivity of the isolated botanical compounds.  
 
 The preparation of nanobioformulation with Trans-caryophyllene and silica 
nanoparticles showed enhanced efficiency of Trans-caryophyllene in controlling the 
population of two major agricultural pests. A patent was filed on synergistic 
nanobioformulation with Trans-caryophyllene and silica nanoparticles useful as insect 
controlling agent and a method of its formulation. Nano silica formulation protects 
the botanicals against degradation, enhance the bioavailability and create high local 
concentrations of the bioactive chemicals in target cells. The formulation controls the 
release rate and prolongs the duration of antifeedant effect of trans-caryophyllene. 
This formulation offer synergistic effect, which gives added advantage for the 
compounds in enhancing antifeedant activity as well as the duration of protection 
against agricultural pests.  
 
 Result revealed that Trans-caryophyllene and its nano-formulations were directly not 
toxic to A. janata, H.armigera and S. litura. But they inhibit the feeding activity of 
130 
the insects leading to pest’s starvation that ultimately leads to its death. Additionally 
the amorphous silica is considered to be safe for human by world health organization 
and US department of agriculture. Therefore their persistence on plant or soil after 
spraying in the field will not have any adverse effects on the environment.  
 
 Regulation of the particle size, morphology, zeta potential, controlled release and 
shelf life of formulation can be easily done by adjusting the concerned parameters, 
e.g., the time of compound loading type of solvent used in the preparation and 
concentrations of precursor’s i.e. isolated compounds and silica nanoparticles.  
 
 Compositions of the isolated bioactive compounds and silica nanoparticles present in 
the nanobiocomposites are found to be directly influencing the size and bioactivity of 
the nanoformulations. Thus, to get the maximum antifeedant activity optimum 
composition of the botanicals were needed in effective nanoformulation.  
 
 The result of present investigation indicated that, there is tremendous scope for 
developing nano-biocomposites in to future pest management as they are 
environmentally safer than the existing synthetic pesticides.  
 
***** 
 
  
 


Quantum-Mechanical Studies to Investigate the Hydrogen B Interactions of Amino Acids with Molecules of Biological Interest

Jain, Aditi

xiii 
 
ABSTRACT  
Drug induced cardiotoxicity have emerged as an important factor for developing cardiovascular 
complications. Present day therapeutics for various lifestyle diseases including cancer, diabetes and 
obesity are reported to have cardiotoxic side effects and require urgent attention of the scientific 
community. Use of natural bioactive compounds having cardioprotective properties for 
supplementing cardiotoxic therapies holds a great potential in this regard. This will improve the 
cardiac health without compromising the therapeutic efficiency of the drugs. With this in mind, the 
present study was designed to analyze the effects of Curcumin, polyphenol derived from Curcuma 
longa and well-known for broad range of protective effects, in drug induced cardiotoxicity. Two 
different classes of drugs with known cardiotoxicity were selected for the study with applications 
in cardiac (hypotension) and non-cardiac (cancer) conditions, namely Levophed (or 
Norepinephrine or NE) and Doxorubicin, respectively.  
Cardiotoxic stress induced by these drugs was firstly confirmed on cardiomyoblasts in 
concentration and time dependent manner by various cell viability assays individually. The effects 
of Curcumin on Doxorubicin and Levophed induced cardiotoxicity were then studied by various 
microscopic, molecular, biochemical and immunological assays. In silico molecular docking 
studies were conducted for Doxorubicin, NE and Curcumin with signaling molecules reported in 
different cardiac stresses to derive the possible signaling involved in Curcumin mediated effects. 
Gene expression analysis was done at transcriptomic and proteomic levels for various cell survival 
and death biomarkers in drug induced in vitro and in vivo models treated with Curcumin at different 
time points.  
We observed that both the selected drugs results in dose mediated stress responses in 
cardiomyoblasts and Curcumin significantly resisted and prevented these effects in a mode 
dependent manner. The in vitro findings were validated in in vivo models and possible signaling 
mechanism of Curcumin mediated effects were derived.  
In conclusion, Curcumin holds a great potential for reducing drug induced cardiotoxicity when 
supplemented with the ongoing therapies having cardiotoxic effects.  
 


CARDIOPROTECTIVE EFFECTS OF CURCUMIN AGAINST DRUG INDUCED TOXICITY

Jhawar, Jitesh

Thesis Title: Intrinsic Noise in Collective Dynamics
Jitesh Jhawar
Indian Institute of Science, Bengaluru
Synopsis
Animal  groups  exhibit  many  emergent  properties  that  are  a  consequence  of  local  interactions.
Linking individual-level behaviour to group-level dynamics has been a question of fundamental
interest from both biological and mathematical perspectives. However, most empirical studies have
focussed on average behaviours ignoring stochasticity at the level of individuals. On the other hand,
conclusions  from theoretical  models  are  often  derived  in  the  limit  of  infinite  systems,  in  turn
neglecting stochastic effects due to finite group sizes. In our study, we use a stochastic framework
that accounts for intrinsic-noise in collective dynamics arising due to (a) inherently probabilistic
interactions  and (b)  finite  number  of  group members.  We derive  equations  of  group dynamics
starting from individual-level probabilistic rules as well as from real data to understand the effects
of such intrinsic noise and the mechanisms underlying collective behaviour. 
First, using the chemical Langevin method, we analytically derive models (stochastic differential
equations) for group dynamics for a variable m that describes the order/consensus within a group.
We assume that organisms stochastically interact and choose between two/four directions. We find
that simple pairwise interactions between individuals lead to intrinsic-noise that depends on the
current state of the system (i.e. a multiplicative or state-dependent noise). Surprisingly, this noise
creates a new ordered state that is absent in the deterministic analogue. 
Next,  focussing  on  small-to-intermediate  sized  groups  (10-100),  we  empirically  demonstrate
intrinsic-noise induced schooling (polarized or highly coherent motion) in fish groups. The fewer
the fish, the greater the intrinsic-noise and therefore the likelihood of alignment. Such empirical
evidence is rare, and tightly constrains the possible underlying interactions between fish. Our model
simulations indicate that fish align with each other one at a time, ruling out other complex higher-
order interactions.
Further, we analyze the method to derive the group-level dynamical equation using simulated data
from two different models of collective behaviour. In doing so we resolve important time-scale
related  issues  with  deriving  the  determinisitic  and  stochastic  components  of  the  mesoscopic
description from the data. 
Broadly,  our  results  demonstrate  that  rather  than  simply  obscuring  otherwise  deterministic
dynamics, intrinsic-noise is fundamental to the characterisation of emergent collective behaviours,
suggesting a need to re-appraise aspects of both collective motion and behavioural inference.


Intrinsic Noise in Collective Dynamics

Ramteke, Darwin Devidas

Chemical speciation of metals in estuarine sediments and 
their accumulation in estuarine benthic organisms 
 
Comprehensive abstract of the thesis is elucidated as follows  
 
Chapter 1 covers the general introduction about metals with special reference to the estuarine 
ecosystem. Toxic metal behavior and the importance of metal speciation over total metal 
concentration are described. This chapter also describes the environmental factors influencing metal 
speciation and bioavailability in estuarine sediments and how the metal from the sediment interact 
with the aquatic flora and fauna. This chapter provides the current state of knowledge on the 
anthropogenic increase of metal input in estuaries, the use of different organisms to understand metal 
bioaccumulation from sediment, applications of chemical extraction techniques to determine metal 
bioavailability. The knowledge gaps based on the current state of knowledge are put forward. The 
objectives of this research work are set in this context demonstrating that metal speciation in 
estuarine sediment determines bioavailability and bioaccumulation in the associated biota.  
The review of the anthropogenic increase of metal in estuarine sediments of India was published in 
Marine Pollution Bulletin Journal (Chakraborty et al., 2014).  
 
Chapter 2 presents detailed information about the study area, the procedure of sampling, storage of 
sediment and tissue of biological organisms, laboratory procedure, analytic techniques used in 
understanding the metal speciation, and the statistical analysis used for the results obtained.  
 
Chapter 3 presents the speciation of Cu and Ni from the mangrove sediments and its bioaccumulation 
in the mangrove roots from Divar Island, Mandovi estuary. This chapter presents that Fe/Mn 
oxyhydroxide and organic phases in the sediments are the major hosting phases for Ni and Cu and 
control its bioavailability in the mangrove system. Further, this study has proposed a plausible 
pathway of Cu and Ni uptake by mangrove roots from the mangrove sediments. This work was 
published in Marine Pollution Bulletin Journal (Chakraborty et al., 2014 and 2015)  
 
Chapter 4 describes Cd speciation from the estuarine sediments and its bioaccumulation in the edible 
oyster (Magallana sp.). Total Cd concentration in water, suspended particulate matter (SPM) and 
sediment was determined. This chapter presents the geochemical fractionation study of bulk and finer 
(< 63 μm) estuarine sediments to estimate Cd bioavailability (chemically). To understand the Cd 
bioaccumulation, estimation of Cd concentration in the softtissues of oysters was carried out. This 
chapter also describes the relationship between Cd in water, SPM, and bulk sediments with 
bioaccumulated Cd in oyster (Magallana sp.). This chapter concludes that bioaccumulation of Cd in 
the oyster increases with the increasing association of Cd in water-soluble, carbonate/bicarbonate, 
and exchangeable forms in the finer particles of the sediments.  
 
Chapter 5 deals with the Kinetic speciation of Cd in the estuarine sediments and its bioaccumulation 
in the edible oyster (Magallana sp.). This chapter presents the Kinetic speciation study of Cd in finer 
fraction of (< 63 μm) estuarine sediments and its relationship with Cd accumulation in soft tissues of 
the edible oyster. The chapter suggests that sedimentary Cd, especially Cd in the finer fraction (< 63 
μm) of the sediment could be responsible for Cd availability from the environment (as reported in 
Chapter 4) and may probably enter into the oyster system through its filter-feeding behavior and 
bioaccumulated in their soft tissues.  
 
Chapter 6 presents the role of environmental factors (such as pH, salinity, Temperature) in governing 
the chemical speciation of Cu and Cd and its bioaccumulation. This chapter describes the effect of 
overlying water column pH on Cu distribution in different geochemical phases of the sediment. It also 
describes the influence of salinity on Cd accumulation in oyster tissue.  
Chapter 7 summarizes the results and provides the overall conclusion of the thesis. 


Chemical speciation of metals in estuarine sediments and their accumulation in estuarine benthic organisms

Cherupally, Dayakar

SYNTHESIS AND BIOLOGICAL STUDIES OF PYRAZOLE, NICOTINALDEHYDE BASED HETEROCYCLIC COMPOUNDS AND DEVELOPMENT OF NOVEL APPROACH FOR PYRAZOLES AND QUINAZOLINES

KORRAPATI, SURESH BABU

DEVELOPMENT OF NEW SYNTHETIC METHODS FOR SOME BIOLOGICALLY IMPORTANT HETEROCYCLES AND EVALUATION OF CYTOTOXIC AND ANTIMICROBIAL POTENTIAL

Owk, Ravi

Preface 
 
 vii 
 
ABSTRACT 
The work carried out in the research tenure has been compiled in the form of thesis entitled 
“Synthesis of Pharmacologically Important Heterocycles via Oxidative Carbon–Carbon 
Bond Cleavage” is divided in to three chapters. 
Chapter 1: Benzimidazoles from Aryl Alkyl Ketones and 2-Amino anilines by an Iodine 
Catalyzed Oxidative C(CO)−C(alkyl) Bond Cleavage. 
This chapter illustrates a novel iodine catalyzed annulation reactions of o-phenylenediamine with 
acetophenone under oxidant and transition metal free conditions. This reaction includes, 
sequential C-N bond formation followed by C(CO)-C(alkyl) bond cleavage. Diversely 
substituted 2-aryl benzimidazoles are obtained in moderate to good yields in single step from 
commercially available acetophenones, propiophenones and phenylacetophenones (Scheme 1). 
Plausible mechanism was proposed based on 
1
H NMR studies and appropriate control 
experiments. 
 
Scheme 1: Synthesis of benzimidazoles from acetophenones and 2-amino anilines 
J. Org. Chem. 2017, 82, 4422−4428. 
Chapter 2: Benzimidazoles and Benzothiazoles from Terminal Aromatic Olefins via 
Palladium Catalysed Oxidative C=C Cleavage: 
In this chapter we have developed a one pot synthetic route for the pharmacologically important 
benzimidazoles and benzothiazoles from readily available styrenes/vinylimidazoles via Pd-
catalyzed, molecular oxygen assisted C=C/C‒N bond cleavage. This process involves sequential 
C=C/C‒N bond cleavage followed by C−N/C−S bond formation for construction of 
benzimidazoles and benzothiazoles from readily available substrates (Scheme 2). In comparison 
Preface 
 
 viii 
 
with the available methods, the present method is highly efficient and easy to operate with high 
substrate scope. 
  
Scheme 2: Our synthetic approach to benzimidazoles and benzothiazoles 
Chapter 3: Copper Catalyzed Domino C‒C Bond Cleavage of 2,3-Unsubstituted 
Indoles/Indolines and Oxindoles via Oxidation and Directed Insertion of 2-
Aminopyridines: A Facile Access to Quinazolinediones. 
This chapter describes an unprecedented Cu-catalyzed domino C‒C bond cleavage of 2,3-
unsubstituted indoles via oxygenation followed by insertion of 2-aminopyridine has been 
described. This method involves the formation of two new C−O and C−N bonds utilizing 
molecular oxygen as sole oxidant for synthesis of pharmacologically important quinazoline-
2,4(1H,3H)‑dione derivatives from commercially available substrates (Scheme 3). It was 
noteworthy that under standard condition indoline also transformed into desired product with 
good yield. Reaction mechanism was proposed based on suitable control experiments and 
analytical technique like LC-MS, mass spectrometry. 
 
Scheme 3: Synthetic approach to quinazoline diones 


Synthesis of Pharmacologically Important Heterocycles via Oxidative Carbon–Carbon bond Cleavage

PASHIKANTI, GOUTHAMI

 
 
“APPLICATION OF BENZYNE CHEMISTRY FOR THE TOTAL 
SYNTHESIS OF CEPHALOTAXINE, 2-AROYL BENZOFURANS 
AND SYNTHETIC STUDIES TOWARDS LABELLED 
NICOTINE” 
 
A SYNOPSIS 
SUBMITTED FOR THE DEGREE OF 
DOCTOR OF PHILOSOPHY 
(IN CHEMISTRY) 
TO 
OSMANIA UNIVERSITY 
 
 
 
BY 
PASHIKANTI GOUTHAMI 
 
Organic Synthesis and Process Chemistry Department 
CSIR-Indian Institute of Chemical Technology 
Hyderabad–500 007 
JUNE 2018 
                                                                                                                    
Synopsis                                                  
I 
 
 
Synopsis 
The thesis entitled “Application of benzyne chemistry for the total synthesis of  
Cephalotaxine, 2-aroyl benzofurans and synthetic studies towards labelled Nicotine” has 
been divided into three chapters. 
Chapter-I : describes about Formal Total Synthesis of (±)-Cephalotaxine and Congeners via 
Aryne Insertion Reaction. 
Chapter-II : describes about Syntheses of 2‑Aroyl Benzofurans through Cascade Annulation 
on Arynes. 
Chapter-III : describes about Synthetic Studies towards Deuterated Nicotine. 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                    
Synopsis                                                  
II 
 
 
Chapter-I : Formal Total Synthesis of (±)-Cephalotaxine and Congeners via Aryne 
Insertion Reaction. 
This chapter describes the  synthesis of (±)-cephalotaxine 1 was isolated by Paudlar and co-
workers from Cephalotaxus harringtonii. One of the esters of cephalotaxine namely 
homoharringtonine (HHT) 2 was approved by Food and Drug Administration (FDA) for 
treatment of orphan leukemia in 2012 (syn. Omacetaxine mepesuccinate, OmaproTM). 
 
Structures of cepahalotaxine and HHT 
The clinical approval of Omacetaxine mepesuccinate 2 as orphan drug, the biological 
signifciance and structural complexity of 1-azabicyclo[5.3.0]decane skeleton prompted us to 
take up the research programme towards the synthesis of cephalotaxine. The formal total 
synthesis of pentacyclic core alkaloid, (±)-cephalotaxine 1 was achieved in eight steps from 
known 2-allylpy-rrolidine-2-carboxaldehyde using aryne insertion reaction as a key step in 
10% overall yield. The developed novel strategy also enabled to access cephalotaxine 
congeners with ease. 
The synthesis of cephalotaxine  started from pyrrolidine-2-carbaldehyde derivative 3 (by 
known literature method from commercially available L-Proline ) was subjected Roskamp 
homologation to synthesize the β-keto ester 4 in 80% yield. Reaction of β-ketoester 4 with 
benzyne generated from methylenedioxy aryne precursor Ia in presence of  CsF allowed a 
smooth -bond insertion reaction to afford compound 5a (scheme 2). The Wacker oxidation 
of 5a with catalytic PdCl2 and CuCl in presence of oxygen atmosphere gave the requisite 
methyl ketone 6a in 70% yield (scheme 1). 
                                                                                                                    
Synopsis                                                  
III 
 
 
 
Scheme 1 
Methyl ketone 6a was subjected to intramolecular aldol reaction triggered by NaH in amyl 
alcohol/benzene solvent mixture and subsequent hydrolysis of ester group were executed in 
one-pot to yield the spiro pyrrolidine 7a. The crude intermediate 7a was subjected to TFA in 
CH2Cl2 to remove the Boc-protection at room temperature. Sequential addition of excess 
DIPEA and EDCl/HOBt in same pot provided pentacyclic frame 8a in 56% isolated yield 
(scheme 2).  
 
Scheme 2 
                                                                                                                    
Synopsis                                                  
IV 
 
 
Reduction of 8a using Adam's catalyst (PtO2) under hydrogen atmosphere provided ketolactam 
9 along with slight amounts of over reduced alcohol as an inseparable mixture. This mixture 
on oxidation with Dess-Martin periodinane allowed us to isolate Hanaoka's intermediate 9 
smoothly in 78% yield for two steps (scheme 2).  
Compound 9 was reacted with BAIB and KOH in MeOH at room temperature furnished 
hydroxyl acetal, reduction of amide with Red-Al in benzene reflux gave amine 10 in 83% yield. 
Finally treatment of acetal 10 with p-TSA in THF reflux to provide Cephalotaxine 1 in 85% 
yield (scheme 3).  
Scheme 3 
Synthesis of cephalotaxine congeners 
The easy access to multiple grams of compound 4 prompted us to attempt insertion reaction 
on various arynes viz, benzyne, dimethoxybenzyne and dimethylbenzyne. Following the 
synthetic route as used for the synthesis of cephalotaxine 1 various aryne precursors Ib-d were 
subjected to smooth aryne insertion reaction with compound 4 afforded 5b-d followed by 
Wacker oxidation gave 6b-d in excellent yields. Subsequent NaH mediated aldol reaction 
resulted in analogs of cephalotaxine 8b-d in good yields (Scheme 4).  
 
                                                                                                                    
Synopsis                                                  
V 
 
 
 
Scheme 4 
 
Chapter-II : Syntheses of 2-aroyl benzofurans through cascade annulation on arynes 
Oxygen containing molecules are an important class of the organic heterocyclic compounds. 
This chapter highlights the synthesis of  benzofuran derivatives through three-component 
coupling reactions. The highly efficient and expedient route for the syntheses of  2-aroyl 
benzofurans via the cascade [2+2] followed by a [4+1] annulation on arynes has been 
developed. The overall transformation proceeded through the formation of ortho-quinone 
methide (o-QM) by the insertion of transient aryne into N,N-dimethylformamide and 
subsequent trapping with sulfur ylide. Sulfur ylides are versatile reagents which can be 
generated from easily accessible α-halo carbonyls and dialkyl sulfides. Many research groups 
elegantly demonstrated the utility of these ylides in cycloaddition reactions. The present 
cascade reaction works well with various sulfur ylides with broad scope and high functional 
group tolerance (Scheme 1). 
 
                                                                                                                    
Synopsis                                                  
VI 
 
 
 
 Mild condition 
 One-step strategy 
 Broad substrate scope 
 High fuctional group tolerance 
Scheme 1 Synthesis of 2-aroyl benzofurans 
 At first instance, the reaction of Kobayashi’s ortho-silyl aryl triflate 1a in DMF with CsF as a 
base at room temperature was treated with sulfonium bromide salt 2a. To our delight, this 
initial attempt produced the desired product 3a in 87% yield, thereby confirming the feasibility 
of our aryne-based approach to 2-aroyl benzofurans. (Scheme 2).  
 
 
Scheme 2 
Next continued by examining alternative sources of fluoride for the in situ formation of 
benzyne,  at various temperatures (Table 1). Increasing the reaction temperature did not show 
any significant variation on yields. While both TBAF (entrie 4) and KF (entries 5 and 7)  
promoted formation of the product, but in low yield. The addition of 18-crown-6 to KF and  
 
                                                                                                                    
Synopsis                                                  
VII 
 
 
CsF did not lead to an improvement in the reaction yield. In the case of CsF, decrease in the 
reaction time was found to have high impact on the efficiency of the reaction (Table 1). Hence, 
after a brief screening, the optimal conditions to be concluded are 1a (1.2 mmol), 2a (1 mmol), 
and fluoride source (4 mmol) in DMF (0.1 M) at room temperature. 
Table 1. Screening for Optimal Reaction Conditionsa 
 
aStandard reaction conditions: The reaction was carried out with 1a (1.2 mmol), 2a (1 mmol), and 
fluoride source (4 mmol) in solvent (0.1 M). bYield of the isolated product. c18-Crown-6 (0.25 
mmol) was used. 
 
With a suitable set of reaction conditions in hand the substrate scope of the reaction was then 
explored. Firstly, the sulfonium bromide salts were investigated – the results of which are 
detailed in Table 2. Substrate scope was then examined under the optimized reaction 
conditions. The reaction was found to be viable for a range of sulfer ylides bearing either  
                                                                                                                    
Synopsis                                                  
VIII 
 
 
electron-donating or electron-withdrawing undergoing smooth cascade annulation in good to 
excellent yields (66-87%).  However, substituents at meta-position gave slightly lower yields. 
With other sulfonium salts bearing heteroaryl groups also proceeded smoothly with good yields 
(Table 2).  
 
Table 2. Substrate scope for sulfur ylidesa,b 
 
 
 
aReation conditions: The reaction was carried out with 1a (1.2 mmol), 2 (1 mmol), and 
fluoride source (4 mmol) in DMF (0.1 M). bYields of products isolated after column 
chromatography 
 
                                                                                                                    
Synopsis                                                  
IX 
 
 
Further investigated the substrate tolerances by examining a series of substituted aryne 
precursors  in combination with sulfonium salt 2  (Table 3). Regardless of electron-donating 
or withdrawing nature of the substituent on the symmetrical aryne precursors 1a-f,  were found 
to produce the expected benzofurans in good yield (69−83%). In case of  unsymmetrically 
substituted aryne precursor, 3-methoxy-2-(trimethylsilyl)phenyl triflate 1g reacted with 
sulfonium salt 2a to give 3u exclusively in 83% yield with complete regiocontrol. However, 
the annulation of 4-methoxytriflate with 2j generated a 9 : 7 mixture of isomeric products.  
Table 3. Substrate scope for benzynea,b 
 
aReaction conditions: The reaction was carried out with 1 (1.2 mmol), 2 (1 mmol), and 
fluoride source (4 mmol) in DMF (0.1 M). bYields of products isolated after column 
chromatography 
                                                                                                                    
Synopsis                                                  
X 
 
 
Synthetic utility 
To demonstrate the synthetic utility of this method, 2-aroyl benzofuran 3b was treated with 
pyridine-3-magnesium bromide to generate potent CYP19 Aromatase inhibitor 4 in 62% yield 
(Scheme 3a). The C1-Wittig olefination of 3a afforded 2-vinylbenzofuran 5 in 87% yield. 
Diels-Alder reaction of compound 5 using methyl acrylate in the presence of Sc(OTf)3 at 110 
oC gave tetrahydrodbenzofuran 6 in 92 % yield with 13:1 ratio of diastereoselectivity (Scheme 
3b).  
 
 
 
Scheme 3 
 
The present cascade reaction was employed for late-stage functionalization on the complex 
bioactive steroid estrone. The sterically crowded aryne precursor 7 synthesized from estrone , 
was subjected to sulfonium salt 2b under standard reaction conditions at 60 oC to afford the 
corresponding product as 7:3 ratio of inseparable regiomers 8a & 8b (Scheme 4). 
 
 
 
 
 
                                                                                                                    
Synopsis                                                  
XI 
 
 
 
Scheme 4 
 
 
Chapter-III : Synthetic Studies towards Deuterated Nicotine 
Nicotine 1 is an alkaloid present in tobacco and a wide variety of other plants. It targets and 
activates nicotinic acetylcholine receptors (nAChRs). Nicotine itself and several analogues 
(Figure 1) have shown therapeutic benefits for a number of central nervous system disorders 
such as Alzheimer’s, Parkinson’s, and Tourette’s diseases. Since the first synthesis by Pictet 
in 1904, numerous syntheses of nicotine and its analogues have been reported. 
 
Figure 1 Nicotine and analogues. 
                                                                                                                    
Synopsis                                                  
XII 
 
 
In this chapter, a new method for the synthesis of nicotine in one-pot has been developed with 
65% overall yield (Scheme 1). The synthesis of nicotine 1 commenced from commercially 
available 3-bromopyridine 5, which  was treated initially with n-butyllithium at –78 °C in diethyl 
ether. N-Methyl succinimide 7 was then added to the resulting lithiated pyridine derivative to 
afford the amido alcohol intermediate at -78 °C. Without isolating the intermediate, the 
reaction mixture was further diluted with THF and subjected to reduction with LiAlH4 at room 
temperature to afford nicotine 1 in 65% overall yield (Scheme 1).  
 
Scheme 1 
This method facilitated the synthesis of fully and partially deuterated nicotine compounds 
(Figure 2). The main interest behind this project is to study the effect of deuterium 
incorporation on nicotine biochemical potency, because selective incorporation of deuterium 
in place of hydrogen has the unique effect of retaining the biochemical potency and selectivity 
to relevant pharmacological targets. In selected cases deuterium incorporation exhibited 
positive effects on biochemical potency by modifying the metabolic rate to substantially alter 
their overall therapeutic profile. Following the same synthetic route (Scheme 1), various 
deuterated nicotine compounds (Figure 2) were also synthesized. 
 
 
 
                                                                                                                    
Synopsis                                                  
XIII 
 
 
 
Figure 2 Deuterated nicotine compounds 
Synthesis of fully deuterated nicotine strated with 3-Bromopyridine-D4 5-D4 was treated with 
n-butyllithium at –78 °C in diethyl ether, to generate lithiated pyridine 6-D4 derivative and was 
added N-CD3 succinimide 7- D7 to afford the corresponding amido alcohol intermediate B at   
-78 °C. Without isolating the intermediate B, the reaction mixture was diluted with THF and 
subjected to reduction with LiAlD4 at room temperature to afford the deuterated nicotine 12 in 
62% overall yield (Scheme 2).   
 
Scheme 2 


APPLICATION OF BENZYNE CHEMISTRY FOR THE TOTAL SYNTHESIS OF CEPHALOTAXINE, 2-AROYL BENZOFURANS AND SYNTHETIC STUDIES TOWARDS LABELLED NICOTINE

MALLADI, SRIKANTH

 iv 
SYNOPSIS 
The work reported in the thesis entitled “Computational Study of Metal Complexes for 
Dye-Sensitized Solar Cells” includes various computational tools employed to understand 
the structure-property relationships in order to develop new class of efficient metal based 
sensitizers. The factors influencing the efficiencies of these dyes are identified and 
discussed in detail for each class of sensitizers. In this thesis, we have mainly dealt with 
three classes of metal sensitizers. The work started with tuning the structural and electronic 
properties of corrole macrocycle by employing push-pull substituents, thereby generating 
a new set of corrole sensitizers. In the second part of thesis, photophysical properties of 
pyridine-benzimidazole ligated ruthenium and heteroleptic phenyl carbene ligated 
ruthenium complexes were investigated. Good performance of these phenyl carbene ligated 
ruthenium complexes has prompted us to employ same ligands for earth-abundant iron 
complexes and to compare both ruthenium and iron based sensitizers. The final part of the 
thesis includes compositional engineering approaches to replace toxic lead with other 
suitable elements in methylammonium lead halide perovskites. The computational results 
obtained by varying the elemental composition of perovskite structure which in turn leads 
to band gap changes and structural distortions are presented. 
 The work done for the thesis is presented in six chapters. A chapter-wise summary 
of the study is given below. 
Chapter 1: Introduction 
Solar energy harvesting technologies have attracted considerable attention as an 
alternative, renewable source of energy, particularly in view of the growing energy needs 
of the world and the depleting reserves of fossil fuels. This chapter outlines the importance 
of solar energy and reviews first, second and third generations of photovoltaic technologies 
available for the conversion of solar radiation into electricity. This chapter comprehends 
the importance of the DSSC technology in view of its cost effective and eco-friendly 
materials. Chapter 1 also includes the strengths and weakness of various porphyrinoid, 
ruthenium complexes and perovskites in harnessing the sunlight and consolidates the latest 
studies reported on metal complexes for DSSC applications.  
 
 v 
Chapter 2: Methodology 
This chapter comprises the description of various theoretical/computational methods 
employed for electronic structure calculations carried out in the thesis. An overview of the 
quantum chemical methods (DFT and Time-Dependent DFT) and their applications to 
study the spectroscopic properties of dye molecules as well as interfacial electron transfer 
process is given in detail. It also summarizes population analysis schemes like Mulliken, 
Hirshfeld, natural bond orbital, and natural transition orbital analysis.  
Chapter 3: Molecular Design of Corrole Based D-π-A Sensitizers for DSSC 
Applications. 
Corrole based metal complexes were under-explored for DSSC applications compared to 
porphyrin sensitizers. This chapter addresses the problem of poor efficiencies of 
metallocorroles, in spite of having many desirable features for DSSC as compared with 
porphyrins. The chapter aims to improve the performance of metallocorrles (Figure 3.1) by 
incorporating D-π-A architecture/push-pull, which will improve unidirectional electron 
flow, attaining maximum hyperpolarizabilities. The study reveals that the nature and 
position of substituents helps in tuning the structure and electronic properties of 
metallocorrole, which further (COR1-COR4) leads to effective and directional charge 
transfer towards anchoring groups, which further leads to efficient electron injection into 
TiO2.  
 
 vi 
 
Figure 3.1 Structures of non-ethynylmetallocorroles systems (Set-A) and ethynylmetallocorrole systems 
(Set-B) considered in this study. 
 
 
 
 
 vii 
Chapter 4: Theoretical Study of Heteroleptic Ruthenium Complexes for DSSC 
Applications 
Due to its favorable photochemical properties, ruthenium complexes have been sought as 
potential sensitizers in manifold studies of DSSC. However, most of these studies were 
done on homoleptic dyes, because of which invariably display poor stability and durability. 
In this chapter, efforts to improve these factors by using heteroleptic ligands for ruthenium 
complex are included. The results demonstrate that a subtle change in the peripheral 
ancillary groups on benzimidazole heteroleptic ligand exerts a substantial effect on the 
excited states and dye regeneration in heteroleptic ruthenium sensitizers (Figure 4.1). The 
influence of these factors on the efficiencies of these dyes has also been explained.  
 
 
Figure 4.1 Ru-complexes containing the heteroleptic pyridine-BI ligand appended with ancillary 
ligands represented in blue color (triphenylamine) 1, (pyrene) 2 and (t-butylbenzyl) 3 that are 
investigated in this study. (Ancillary ligands given in blue color) 
Chapter 5: Towards the Development of Iron Photosensitizers with Bis-coordinated 
C^N Ligands for DSSC Applications 
In continuation of studies reported in Chapter 4, strategies adopted to bring down the cost 
involved in tedious synthetic protocols of traditional ruthenium dyes are included in 
Chapter 5. A rational approach is included in this chapter towards the design of efficient 
iron sensitizers based on heteroleptic phenyl carbene ligands, which involves simple 
 viii 
synthetic protocols and inexpensive starting precursors. Here heteroleptic phenyl carbene 
ligands have been substituted with electron-withdrawing CF3, donating -N(CH3)2 and 
benzothiazine annulation of carbene ring (Figure 5.1). The substitution effects on the 
electronic structure and optical properties of Fe- and Ru-complexes have been investigated 
using DFT, TD-DFT, energy decomposition analysis and spin density distribution analysis.  
 
Figure 5.1 Heteroleptic phenyl carbene ligands represented in blue color (C^N) containing iron (FC) and 
ruthenium (TC) complexes.  
Chapter 6: Exploring Earth-abundant Elements to Replace Toxic Lead in Perovskite 
Solar Cells 
Perovskite solar cell technology (PSC) which stem from DSSC has been selected as one of 
the biggest scientific breakthroughs of recent times. Perovskite solar cells (PSCs) which 
integrate DSSC technology have recently achieved the efficiencies greater than 20%. 
However lead toxicity and long-term stability are major concerns for large scale 
fabrication. The most commonly studied perovskite absorber is methylammonium lead 
trihalide (CH3NH3PbX3, where X is a halogen ion such as I
-, Br-,Cl-). Hybrid organic lead 
halide perovskite with multi valley and multi band gap material as a reference and Sn 
atomic layered compounds are studied and compared with experimental band gaps (Figure 
6.1) in this chapter. Electronic properties reveal that iodine 5p electrons can be photo-
excited to Sn 5p and Pb 6p empty states. Pure lead halide perovskites having inverse band 
 ix 
structure is transformed to normal band structure by doping with Ba2+ (5s25p64d10s0). 
Barium layered perovskites with other divalent cations (lead, tin, germanium, zinc, 
cadmium, mercury) found to exhibit direct band gaps. Moreover, the band gaps for these 
barium interlaced perovskites structure found to be direct band gaps and are in the range 
of 2-3 eV.  
 
 
 
 MAPbI3  
   
i)MA2BB
1I6-L ii) MA2 BB
1I6-C iii)MA2 BB
1I6-R 
 
Figure 6.1 Perovskite compound with three types of ordering of BI6 (grey) and B1I6 (blue) octahedral in i) 
horizontal (010), ii) columnar (100) and iii) rock salt layering type (111). 
 
Publications included in the thesis 
1 Molecular design of corrole-based D-π-A Sensitizers for dye-sensitized solar cell 
applications.Srikanth, M.; Sastry, G. N.; Soujanya, Y. Int. J. Quantum Chem. 2015, 
115, 745–752. 
2 Benzimidazole-functionalized ancillary ligands for heteroleptic Ru(II) complexes: 
synthesis, characterization and dye-sensitized solar cell applications.Jella, T.; 
Srikanth, M.; Bolligarla, R.; Soujanya, Y.; Singh, S. P.; Giribabu, L. Dalton Trans. 
2015, 44, 14697–14706. 
3 Heteroleptic Ru(II) cyclometalated complexes derived from benzimidazole-phenyl 
carbene ligands for dye-sensitized solar cells: an experimental and theoretical 
approach.Jella, T.; Srikanth, M.; Soujanya, Y.; Singh, S. P.; Giribabu, L.; Islam, A.; 
 x 
Han, L.; Bedja, I.; Gupta, R. K. Mater. Chem. Front. 2017, 1, 947–957. 
4 Towards the Development of Iron Photosensitizers with Bis-coordinated C^N 
Ligands for DSSC Applications.Srikanth, M.; Soujanya, Y.  (submitted to Phys. 
Chem. Chem. Phys.). 
5 Exploring Earth-abundant Elements to Replace Toxic Lead in Perovskite Solar 
Cells. Srikanth, M.;  Soujanya, Y. (Manuscript underpreparation). 


Not a member yet